JP4982842B2 - Method for producing lamellarin sulfate and related compounds - Google Patents

Description

The present invention relates to a method for producing lamellarins having integrase inhibitory activity and promising as an antiretroviral agent. Specifically, the present invention relates to a method for producing lamellarin α20- sulfate and related compounds.

  Three types of enzymes, reverse transcriptase, protease, and integrase, are essential for the replication of retroviruses such as human immunodeficiency virus (HIV). Of these, the former two inhibitors of enzymes are widely used in AIDS treatment. However, resistance viruses against these inhibitors have emerged, and there is a need for the development of new anti-HIV agents that use integrase inhibition as a new mechanism of action. Since integrase does not exist in human cells, selective inhibitors of integrase are likely to be AIDS drugs with fewer side effects compared to conventional anti-HIV agents, but they are still approved as pharmaceuticals There is no integrase inhibitor and rapid development is required.

Lamellarin α20- sulfate represented by the following formula is a natural product isolated from Arabian sea squirts by Faulkner et al. This compound not only exhibits selective integrase inhibitory activity, but also inhibits actual HIV growth (IC ₅₀ = 8 μM ). Moreover, it has low cytotoxicity (LD ₅₀ = 274 μM ) and is considered to be a lead compound of a novel anti-HIV agent with high safety (Non-patent Document 1).

  However, since it is difficult to obtain this compound in large quantities from natural sea squirts, derivatization from a naturally derived compound is not practical. Therefore, from the viewpoint of developing a new anti-HIV agent, there is a demand for the development of a highly flexible chemical synthesis method that is efficient and can be easily deployed to various types of rims.

Journal of Medicinal Chemistry, 1999, vol. 42, p.1901-1907 Bioorganic & Medicinal Chemistry, 2002, vol. 10, p.3285-3289 Tetrahedron Letters, 2003, vol. 44, p.4443-4446

Currently, the only technique for obtaining lamellarin α20- sulfate is extraction from Arabian sea squirts as described above (Non-patent Document 1). Faulkner et al. Reported an attempt at chemical synthesis, but the selective sulfation of the 20-position hydroxyl group of lamellarin α was not successful, and only a small amount of lamellarin α-13,20 disulfate was obtained ( Non-patent document 2).

The present inventors diligently studied in view of the above problems. As a result, an original construction method having high flexibility and versatility of the lamellarin skeleton was established (Non-patent Document 3), and an intermediate in which the 13-position and 20-position hydroxyl groups of lamellarin α were protected with different protecting groups using this technique. Was synthesized. Furthermore, the synthesis of lamellarin α20- sulfate was succeeded for the first time by combining the selective deprotection of such an intermediate with a sulfation method via a sulfate ester intermediate, and the present invention was completed.
That is, the present invention is as follows.
[1] General formula (II)

(In the formula, ring A may have a substituent, and R ¹ may have a lower alkyl group that may be halogenated, an aryl group that may have a substituent, or a substituent. X ¹ represents a halogen atom, a trifluoromethanesulfonyloxy group or an arylsulfonyloxy group optionally having substituent (s)) (hereinafter also referred to as compound (II)). And general formula (III)

(In the formula, ring B may have a substituent, and R ² represents a hydrogen atom, a lower alkyl group which may be halogenated, or may be bonded to each other to form a ring. Wherein P ¹ represents a hydroxyl-protecting group) (hereinafter also referred to as compound (III)) is reacted in the presence of a transition metal catalyst.

(In the formula, each symbol has the same meaning as described above.) A method for producing a compound represented by the following (hereinafter also referred to as compound (IV)).
[2] The production method of the above-mentioned [1], wherein P ¹ is an isopropyl group.
[3] Compound (IV) and general formula (V)

(In the formula, ring C may have a substituent, and R ³ represents a hydrogen atom, a lower alkyl group which may be halogenated, or may be bonded to each other to form a ring. P ² represents a hydroxyl protecting group that can be deprotected under conditions where P ¹ is not deprotected, and P ³ represents a hydroxyl protecting group that can be deprotected under conditions where P ¹ and P ² are not deprotected. A compound represented by the general formula (VI), characterized in that a compound (hereinafter also referred to as compound (V)) is reacted in the presence of a transition metal catalyst.

(In the formula, each symbol has the same meaning as described above.) A method for producing a compound represented by the following (hereinafter also referred to as compound (VI)).
[4] The production method of the above-mentioned [3], wherein P ¹ is an isopropyl group, P ² is a benzyl group, and P ³ is a methoxymethyl group.
[5] the compound P ³ selectively deprotected in (VI), and forming a lactone ring performs transesterification intramolecularly general formula (VII)

(In the formula, each symbol has the same meaning as described above.) A process for producing a compound represented by the formula (hereinafter also referred to as compound (VII)).
[6] The production method of the above-mentioned [5], wherein P ¹ is an isopropyl group, P ² is a benzyl group, and P ³ is a methoxymethyl group.
[7] A compound of the general formula (VIII), characterized by hydrolyzing the compound (VII)

(In the formula, each symbol has the same meaning as described above.) A method for producing a compound represented by the formula (hereinafter also referred to as compound (VIII)).
[8] The production method of the above-mentioned [7], wherein P ¹ is an isopropyl group and P ² is a benzyl group.
[9] General formula (IX), characterized by decarboxylation of compound (VIII)

(In the formula, each symbol has the same meaning as described above.) A method for producing a compound represented by the following (hereinafter also referred to as compound (IX)).
[10] The production method of the above-mentioned [9], wherein P ¹ is an isopropyl group and P ² is a benzyl group.
[11] A compound represented by the general formula (X), wherein the compound (IX) is subjected to oxidative ring closure

(In formula, each symbol is synonymous with the above.) The manufacturing method of the compound (henceforth a compound (X)) represented.
[12] The production method of the above-mentioned [11], wherein P ¹ is an isopropyl group and P ² is a benzyl group.
[13] General formula (XI) characterized by oxidizing compound (X)

(In the formula, each symbol has the same meaning as described above.) A method for producing a compound represented by the following (hereinafter also referred to as compound (XI)).
[14] The production method of the above-mentioned [13], wherein P ¹ is an isopropyl group and P ² is a benzyl group.
[15] The compound is characterized by selectively deprotecting a P ² of (XI), the general formula (XII)

(In the formula, each symbol has the same meaning as described above.) A method for producing a compound represented by the following (hereinafter also referred to as compound (XII)).
[16] The production method of the above-mentioned [15], wherein P ¹ is an isopropyl group and P ² is a benzyl group.
[17] Compound (XII) is converted to general formula (XIII)

(Wherein P ⁴ represents a sulfonic acid protecting group that is not deprotected under the condition that P ¹ is deprotected), and is reacted with a compound (hereinafter also referred to as compound (XIII)). General formula (XIV)

(Wherein each symbol has the same meaning as described above). A method for producing a compound represented by the following (hereinafter also referred to as compound (XIV)).
[18] The production method of the above-mentioned [17], wherein P ¹ is an isopropyl group and P ⁴ is a 2,2,2-trichloroethyl group.
[19] A compound represented by the general formula (XV), wherein P ¹ of the compound (XIV) is selectively deprotected.

(Wherein each symbol has the same meaning as described above). A method for producing a compound represented by the formula (hereinafter also referred to as compound (XV)).
[20] The production method of the above-mentioned [19], wherein P ¹ is an isopropyl group and P ⁴ is a 2,2,2-trichloroethyl group.
[21] a compound, wherein the deprotecting the ^{P 4} of (XV), the general formula (I)

(Wherein each symbol has the same meaning as described above), or a method for producing a salt thereof (hereinafter also referred to as compound (I)).
[22] The production method of the above-mentioned [21], wherein P ⁴ is a 2,2,2-trichloroethyl group.
[23] Production according to [1], [3], [5], [7], [9], [11], [13], [15], [17], [19] and [21] A process for producing compound (I) or a salt thereof, comprising at least one process selected from the processes.
[24] Production according to [1], [3], [5], [7], [9], [11], [13], [15], [17], [19] and [21] A process for producing compound (I) or a salt thereof, characterized by comprising a process.
[25] General formula (IV)

(In the formula, the A ring and the B ring may each independently have a substituent, and R ¹ may be a halogenated lower alkyl group, an optionally substituted aryl group, or a substituted group. An aralkyl group which may have a group, X ¹ represents a halogen atom, a trifluoromethanesulfonyloxy group or an arylsulfonyloxy group which may have a substituent, and P ¹ represents a hydroxyl protecting group. ) A compound represented by
[26] Ring A and ring B may each independently have 1 to 3 substituents selected from an alkoxy group, an optionally halogenated alkyl group, and a halogen atom, and X ¹ is trifluoromethane. The compound of the above-mentioned [25], which is a sulfonyloxy group and P ¹ is an isopropyl group.
[27] General formula (VI)

(In the formula, A ring, B ring and C ring may each independently have a substituent, and R ¹ may be a halogenated lower alkyl group or a substituent aryl. An aralkyl group which may have a group or a substituent, P ¹ represents a hydroxyl protecting group, P ² represents a hydroxyl protecting group which can be deprotected under the condition that P ¹ is not deprotected, and P ³ represents P ¹ and P ² represent a hydroxyl-protecting group that can be deprotected under the condition that is not deprotected.)
[28] The A ring, the B ring, and the C ring may each independently have 1 to 3 substituents selected from an alkoxy group, an optionally halogenated alkyl group, and a halogen atom, and P ¹ The compound according to [27] above, wherein is an isopropyl group, P ² is a benzyl group, and P ³ is a methoxymethyl group.
[29] General formula (VII ')

(In the formula, A ring, B ring and C ring may each independently have a substituent, and R ⁴ is a hydrogen atom, a carboxyl group or —CO ₂ R ¹ (where R ¹ is halogenated) A lower alkyl group which may be substituted, an aryl group which may have a substituent or an aralkyl group which may have a substituent.), P ¹ represents a hydroxyl protecting group, and P ² represents A compound represented by the following: a hydroxyl protecting group that can be deprotected under the condition that P ¹ is not deprotected.
[30] The A ring, the B ring, and the C ring may each independently have 1 to 3 substituents selected from an alkoxy group, an optionally halogenated alkyl group, and a halogen atom, and P ¹ The compound according to [29] above, wherein is an isopropyl group and P ² is a benzyl group.
[31] General formula (I ′)

(In the formula, A ring, B ring and C ring may independently have a substituent, - - - - represents a single bond or a double bond, P 1 ^'is a hydrogen atom or a hydroxyl protecting group P ^{2 ′} is a hydrogen atom, a hydroxyl protecting group deprotectable under conditions where P ^{1 ′} is not deprotected, or —SO ₃ P ⁴ (where P ⁴ is deprotected under conditions where P ^{1 ′} is deprotected). A non-protected sulfonic acid protecting group.), Except that P ^{1 ′} and P ^{2 ′} are simultaneously a hydrogen atom.) Or a pharmaceutically acceptable salt thereof.
[32] The A ring, the B ring, and the C ring may each independently have 1 to 3 substituents selected from an alkoxy group, an optionally halogenated alkyl group, and a halogen atom, and P ¹ The compound of the above-mentioned [31] or a pharmaceutically acceptable salt thereof, wherein ^' is an isopropyl group and P ^2' is a hydrogen atom, a benzyl group or a 2,2,2-trichloroethoxysulfonyl group.
[33] The A ring, the B ring, and the C ring may each independently have 1 to 3 substituents selected from an alkoxy group, an optionally halogenated alkyl group, and a halogen atom, and P ¹ The compound according to [31] above, wherein ^' is a hydrogen atom and P ^2' is a 2,2,2-trichloroethoxysulfonyl group, or a pharmaceutically acceptable salt thereof.
[34] A pharmaceutical composition comprising the compound according to any one of [31] to [33] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
[35] An antiretroviral agent comprising the compound according to any of [31] to [33] above or a pharmaceutically acceptable salt thereof as an active ingredient.
[36] The antiretroviral agent according to the above [35], which is an anti-HIV agent.
[37] The antiretroviral agent according to the above [35], which is an anti-HTLV-1 agent.
[38] The antiretroviral agent according to [37] above, which is a prophylactic / therapeutic agent for HTLV-1-related myelopathy (HAM).
[39] An integrase inhibitor comprising as an active ingredient the compound according to any of [31] to [33] or a pharmaceutically acceptable salt thereof.
[40] The inhibitor of [39] above, which is an HIV integrase inhibitor.
[41] The inhibitor of the above-mentioned [39], which is an HTLV-1 integrase inhibitor.

The present invention provides the world's first method for synthesizing lamellarin α20- sulfate. Since the reaction at each stage in this method can be easily scaled up, a large amount of lamellarin α20- sulfate required for pharmacological tests and the like can be supplied.
The method of the present invention requires 11 steps, but is a compound that can be easily synthesized by known methods from 2-phenylethylamines such as 2- (3,4-dimethoxyphenyl) ethylamine, which is an inexpensive commercial product ( It is a practical synthesis method that uses II) as a raw material and has a very high total yield of 24% to lamellarin α20- sulfate and can sufficiently withstand industrial applications.
Furthermore, by changing the structure of the aromatic ring part and its substituent of the starting material 2-phenylethylamine and the compound (III) and compound (V) which are partners of the cross-coupling reaction with the compound (II) A variety of lamellarin α20- sulfate analogues can be synthesized, and application to structure-activity relationship studies has made it possible to create anti-HIV agents with higher activity and lower toxicity.

Hereinafter, the present invention will be discussed in detail.
The lower alkyl group which may be halogenated in R ¹ , R ² and R ³ may have 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom). A straight or branched alkyl group having 1 to 9 carbon atoms, preferably 1 to 4 carbon atoms (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl) Specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, 2,2,2-trichloroethyl and the like can be mentioned. Preferably methyl or ethyl.
As the aryl group which may have a substituent in R ¹ , R ² and R ³ , a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.), a halogen atom (eg, fluorine atom, Chlorine atoms, etc.), C _1-6 alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.) and the like, which may have 1 to 3 substituents, preferably 6 to 20 carbon atoms, preferably Examples include 6 to 10 aryl groups (eg, phenyl, naphthyl, etc.), and specific examples include phenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, and the like.
Examples of the aralkyl group which may have a substituent for R ¹ , R ² and R ³ include a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.), a halogen atom (eg, fluorine atom, A chlorine atom, etc.), a C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.) and the like. 7-10 aralkyl groups (eg, benzyl, phenylethyl, etc.) can be mentioned, and specific examples include benzyl, 1-phenylethyl, 2-phenylethyl, 4-methoxybenzyl and the like.

Examples of the halogen atom for X ¹ include a chlorine atom, a bromine atom, and an iodine atom, preferably a bromine atom or an iodine atom.
Examples of the arylsulfonyloxy group which may have a substituent for X ¹ include benzenesulfonyloxy and p-toluenesulfonyloxy.

Examples of the ring formed by bonding to each other in R ² and R ³ include pinacol borane and catechol borane.

The A ring, B ring and C ring may have a substituent at a position where the substituent is not clearly shown in each chemical formula. Examples of such substituents include the following.
(A) Alkyl group which may be halogenated: a linear or branched alkyl group having 1 to 9, preferably 1 to 4 carbon atoms which may be substituted with a halogen atom (eg, fluorine atom, chlorine atom, etc.) Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, trifluoromethyl, pentafluoroethyl, and the like, preferably methyl or ethyl.
(B) Aryl group: An aryl group having 6 to 20 carbon atoms, preferably 6 to 10 carbon atoms, such as phenyl and naphthyl.
(C) Aralkyl group: Aralkyl groups having 7 to 20 carbon atoms, preferably 7 to 10 carbon atoms, such as benzyl and phenylethyl.
(D) Alkoxy group: linear or branched alkoxy group having 1 to 9, preferably 1 to 4 carbon atoms (excluding isopropoxy group, sec-butoxy group, tert-butoxy group), for example, methoxy, Examples include ethoxy, propoxy, butoxy, isobutoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy, and preferably methoxy or ethoxy.
(E) Aryloxy group: An aryloxy group having 6 to 20 carbon atoms, preferably 6 to 10 carbon atoms, such as phenoxy and naphthyloxy.
(F) Aralkyloxy group: Aralkyl groups having 7 to 20 carbon atoms, preferably 7 to 10 carbon atoms (excluding benzyloxy and trityloxy), such as 2-phenylethyloxy.
(G) Halogen atom: Examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
(H) Hydroxy group (in the case of inhibiting the reaction in each step, it may be protected with a protecting group (eg, isopropyl group, benzyl group, etc.))
(I) Amino group (when the reaction in each step is inhibited, it may be protected with a protecting group (eg, tert-butoxycarbonyl group, benzyloxycarbonyl group, etc.))
(J) Monoalkylamino: a linear or branched alkylamino group having 1 to 9, preferably 1 to 4 carbon atoms, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec- Examples include butylamino, tert-butylamino, pentylamino, isopentylamino, neopentylamino, hexylamino and the like.
(K) dialkylamino: an amino group having 1 to 9 carbon atoms, preferably 1 to 4 linear or branched, identical or different alkyl groups, such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, Examples thereof include dibutylamino, diisobutylamino, disec-butylamino, ditert-butylamino, dipentylamino, diisopentylamino, dineopentylamino, dihexylamino, N-methyl-N-ethylamino and the like.
(L) Alkylthio: linear or branched alkylthio group having 1 to 9, preferably 1 to 4 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio , Isopentylthio, neopentylthio, hexylthio and the like.
(M) Alkylsulfonyl: a linear or branched alkylsulfonyl group having 1 to 9, preferably 1 to 4 carbon atoms, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butyl Examples include sulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, hexylsulfonyl and the like.

The substituent is preferably an alkoxy group, particularly preferably methoxy or ethoxy.
The number of substituents in the A ring, B ring, and C ring is not particularly limited, but is preferably 1 to 3, and more preferably 1 or 2. When there are two or more substituents on the same ring, they may be the same or different.

As the hydroxyl protecting group for P ¹ , P ² and P ³ , any combination of hydroxyl protecting groups known per se can be adopted as long as the following conditions (1) and (2) are satisfied.
Condition (1): P ² is a hydroxyl protecting group that can be deprotected under the condition that P ¹ is not deprotected.
Condition (2): P ³ is a hydroxyl-protecting group that can be deprotected under the condition that P ¹ and P ² are not deprotected.
Specifically, as long as the conditions (1) and (2) are satisfied, various protecting groups described in Chapter 3 of Protective Groups in Organic Synthesis 3rd edition, Wiley, John & Sons, Incorporated (1999) are used. (However, the methyl group is excluded.) For example, methoxymethyl group, benzyloxymethyl group, methoxyethoxymethyl group, 2- (trimethylsilyl) ethoxymethyl group, methylthiomethyl group, phenylthiomethyl group, 2,2-dichloro- 1,1-difluoroethyl group, tetrahydropyranyl group, phenacyl group, p-bromophenacyl group, cyclopropylmethyl group, allyl group, isopropyl group, cyclohexyl group, tert-butyl group, benzyl group, 2,6-dimethylbenzyl group 4-methoxybenzyl group, o-nitrobenzyl group, 2,6-dichlorobenzyl group, 4- (dimethylamino) Minocarbonyl) benzyl group, 9-anthrylmethyl group, 4-picolyl group, heptafluoro-p-tolyl group, tetrafluoro-4-pyridyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group Acetyl group, levulinoyl group, pivaloyl group, benzoyl group, 9-fluorenecarbonyl group, methoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, dimethylphosphonyl group, dimethyl Examples include a combination selected from the group consisting of a thiophosphonyl group, a methanesulfonyl group, a p-toluenesulfonyl group, and the like.
Table 1 below lists preferred combinations of hydroxyl protecting groups.

  In Table 1 above, no. 1 is a particularly preferred combination of protecting groups.

Any sulfonic acid protecting group known per se can be adopted as the sulfonic acid protecting group for P ⁴ as long as the following condition (3) is satisfied.
Condition (3): P ⁴ is a sulfonic acid protecting group that is not deprotected under the condition that P ¹ is deprotected.
Examples of the sulfonic acid protecting group satisfying such conditions include 2,2,2-trichloroethyl group and 2- (trimethylsilyl) ethyl group, and 2,2,2-trichloroethyl group is particularly preferable.

  Compound (I) is a sulfuric monoester, and may be in the form of a salt with a base. Examples of such salts include alkali metal salts (for example, sodium salts and potassium salts); alkaline earth metal salts (for example, calcium salts and magnesium salts); ammonium salts; organic base salts (for example, trimethylamine salts, triethylamine salts, pyridine salts, Picolin salts, dicyclohexylamine salts, etc.); salts with basic amino acids (lysine salts, arginine salts, etc.) and the like.

  The method of the present invention is shown in the following scheme.

  Compound (II) which is a raw material of the present invention can be easily synthesized from a 2-phenylethylamine derivative according to the method described in Tetrahedron Letters, 2003, vol.44, p.4443-4446.

(In the formula, each symbol has the same meaning as described above.)
Below, each process is demonstrated in detail.
When a substituent (hydroxy group, amino group, etc.) that inhibits the reaction is present in the starting compound of each step, a protecting group is introduced in advance, or the substituent is known per se before each step. You may protect by. Such protecting groups include isopropyl, benzyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like.
The protecting group may be deprotected by a method known per se after the final step or before or after any step, or may be deprotected under reaction conditions in each step. When each step is deprotected under reaction conditions, it may be further reprotected.
The compound obtained in each of the following steps can be isolated and purified (for example, extraction, washing, concentration, crystallization, recrystallization, column chromatography, thin layer chromatography, etc.) by a conventional method. Moreover, it can also attach | subject to a next process, without isolating or refine | purifying in particular.

1. Process (1)
Step (1) is a method for producing compound (IV) in which compound (II) and compound (III) are reacted in the presence of a transition metal catalyst. Step (1) can be performed according to the so-called Suzuki coupling method (J. Chem. Soc., Chem. Commun. 1979, 866). Specifically, it can be carried out by mixing compound (II), compound (III) and a transition metal catalyst in a solvent. The order of adding each sample is not particularly limited.

  Compound (III) can be prepared by lithiation of the corresponding aryl bromide or conversion to a Grignard reagent followed by reaction with borate esters. The amount of compound (III) to be used is generally 1 equivalent to 1.5 equivalents, preferably 1 equivalent to 1.1 equivalents, relative to compound (II). When the amount is larger than this range, a large number of dicouples are generated, which is not preferable.

Examples of the transition metal catalyst used in the step (1) include zero values such as (PPh ₃ ) ₄ Pd, PdCl ₂ (PPh ₃ ) _2, PdCl ₂ (dppf) ₂ , Pd (OAc) ₂ / Ph ₃ P, or A divalent palladium catalyst is preferred. The amount of transition metal catalyst used is usually 0.001 equivalents to 0.2 equivalents, preferably 0.02 equivalents to 0.05 equivalents, relative to compound (II). If the amount is less than this range, the reaction is difficult to proceed.

  In step (1), a base is added to activate compound (III) and promote the reaction. Examples of the base include sodium carbonate, potassium carbonate, cesium fluoride, cesium carbonate, tripotassium phosphate, thallium carbonate and the like, and sodium carbonate or potassium carbonate is preferable. The amount of the base to be used is generally 3 equivalents to 20 equivalents, preferably 5 equivalents to 8 equivalents, relative to compound (III).

  The solvent used in step (1) is not particularly limited as long as it does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, methyl tert-butyl ether, 1,4-dioxane; toluene; Examples thereof include dimethylformamide; dimethyl sulfoxide; methanol; water alone or a mixed solvent. The usage-amount of a solvent is the range of 5-50L with respect to 1 mol of compounds (II).

  The reaction temperature in the step (1) is usually from 30 ° C to 150 ° C, but preferably from 50 ° C to 100 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

2. Process (2)
Step (2) is a method for producing compound (VI) in which compound (IV) and compound (V) are reacted in the presence of a transition metal catalyst. Step (2) can be performed in the same manner as in step (1). Details are omitted.

3. Process (3)
Step (3) is a process for producing compound (VII) in which P ³ of compound (VI) is selectively deprotected. Step (3), in combination ^P 1, ^{P 2} and ^{P 3} which satisfies the above conditions (1) and condition (2), if the reaction conditions that can selectively deprotected only ^{P 3,} particularly limited Can be done without.
Specifically, Protective Groups in Organic Synthesis 3rd edition , Wiley, John & Sons, Incorporated (1999) Chapter 3 Deprotection Method P ³ described or cited in the like.
Here, deprotection of a methoxymethyl group, which is a representative protecting group, will be described, but the step (3) is not limited to the deprotection method.
Note that lactonization proceeds by the transesterification reaction with the ester group at the 2-position of the pyrrole ring together with deprotection of P ³ to obtain compound (VII).

  Deprotection of the methoxymethyl group can be carried out, for example, by mixing compound (VI) and an acid in a solvent. The order of adding each sample is not particularly limited.

  Examples of the acid include hydrochloric acid, p-toluenesulfonic acid, camphorsulfonic acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like, and hydrochloric acid, p-toluenesulfonic acid and the like are preferable. The amount of the acid to be used is generally 0.1 equivalent to 100 equivalents, preferably 10 equivalents to 30 equivalents, relative to compound (VI). If the amount is less than this range, the reaction is difficult to proceed.

  Any solvent may be used as long as it does not inhibit the reaction. For example, alcohol solvents such as methanol, ethanol, propanol, and isopropanol; water; acetic acid alone or these protic solvents and tetrahydrofuran, diethyl ether, 1, 2 -Ether solvents such as dimethoxyethane, methyl tert-butyl ether, 1,4-dioxane; and mixed solvents with dimethylformamide and the like. The usage-amount of a solvent is the range of 5-50L with respect to 1 mol of compounds (VI).

  The reaction temperature is usually 30 ° C to 120 ° C, but 50 ° C to 80 ° C is preferable. The reaction time is usually 0.5 hours to 10 hours, although it depends on the reagents used and the reaction temperature.

4). Step (4)
Step (4) is a method for producing compound (VIII) in which compound (VII) is hydrolyzed. Specifically, it can be carried out by mixing compound (VII) and a base in a solvent. The order of adding each sample is not particularly limited.

  Examples of the base include sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like, and sodium hydroxide or potassium hydroxide is preferable. The amount of the base to be used is generally 10 equivalents to 300 equivalents, preferably 250 equivalents to 300 equivalents, relative to compound (VII). If the amount is less than this range, the reaction is difficult to proceed.

  The solvent used in the step (4) may be any solvent that does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diglyme; methanol, 2-propanol , 2-methyl-2-propanol, ethylene glycol and other alcohols; water and the like alone or in combination. The amount of the solvent to be used is in the range of 10 to 50 L with respect to 1 mol of compound (VII).

  The reaction temperature in step (4) is usually from 50 ° C to 100 ° C, but preferably from 75 ° C to 100 ° C. The reaction time is usually 1 hour to 5 hours, although it depends on the reagents used and the reaction temperature.

  After completion of the reaction, the resulting crude product may be partially converted to a hydroxy-carboxylic acid by cleavage of the lactone ring, so that it is preferably lactonized by treatment with an acid in a solvent.

  Examples of the acid include p-toluenesulfonic acid, camphorsulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like, and p-toluenesulfonic acid is preferable. The amount of the acid to be used is generally 0.1 equivalent to 1 equivalent, preferably 0.4 equivalent to 0.6 equivalent, relative to compound (VII).

  Any solvent may be used as long as it does not inhibit the reaction. Examples thereof include halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane; tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, methyl tert-butyl ether, 1, An ether solvent such as 4-dioxane; benzene; a single solvent such as toluene or a mixed solvent may be used. The amount of the solvent to be used is in the range of 10 to 100 L with respect to 1 mol of compound (VII).

  The reaction temperature for the acid treatment is usually 20 ° C to 100 ° C, but 40 ° C to 60 ° C is preferable. The reaction time is usually 0.5 hours to 2 hours, although it depends on the reagents used and the reaction temperature.

5. Process (5)
Step (5) is a method for producing compound (IX) in which compound (VIII) is decarboxylated.
Step (5) may employ any method as long as it is a reaction condition for decarboxylation of compound (VIII).
Although a typical method is demonstrated below, process (5) is not limited to the said method.

  Decarboxylation can be performed, for example, by mixing compound (VIII) and a copper compound in a solvent or without a solvent. The order of adding each sample is not particularly limited.

  Examples of the copper compound include copper, copper (I) oxide, copper (II) oxide, and copper (II) chloride, with copper (I) oxide being preferred. The usage-amount of a copper compound is 1 equivalent-5 equivalent normally with respect to compound (VIII), Preferably it is 1 equivalent-1.5 equivalent. If the amount is less than this range, the reaction is difficult to proceed.

  In step (5), since heating is required, the reaction is preferably carried out in a high boiling nitrogen-containing polar solvent. Examples of the high boiling nitrogen-containing polar solvent include quinoline, N, N-dimethylacetamide, N-methylpyrrolidone, 2,6-lutidine, s-collidine and the like, and quinoline is preferable. The amount of the high-boiling nitrogen-containing polar solvent used is usually in the range of 5 L to 20 L with respect to 1 mol of compound (VIII).

  The reaction temperature is usually 150 ° C to 250 ° C, but 180 ° C to 220 ° C is preferable. The reaction time is usually 5 minutes to 30 minutes, although it depends on the reagent used and the reaction temperature.

6). Step (6)
Step (6) is a method for producing compound (X) in which compound (IX) is oxidized and cyclized.
As the step (6), any method can be adopted as long as the reaction condition is such that the compound (IX) undergoes oxidative ring closure.
Although a typical method is demonstrated below, a process (6) is not limited to the said method.

  Oxidative ring closure can be performed, for example, by mixing compound (IX) and an oxidizing agent in a solvent. The order of adding each sample is not particularly limited.

  As the oxidizing agent, [bis (trifluoroacetoxy) iodo] benzene, [bis (acetoxy) iodo] benzene, polyvalent iodine compounds such as o-iodoxybenzoic acid, vanadium fluoride, and the like are preferable. The amount of the oxidizing agent to be used is generally 1 equivalent to 3 equivalents, preferably 1 equivalent to 1.5 equivalents, relative to compound (IX). If the amount is less than this range, the reaction is difficult to proceed.

  When a polyvalent iodine compound is used in step (5), a Lewis acid is preferably added to activate the polyvalent iodine compound. Examples of the Lewis acid include boron trifluoride ether complex, trimethylsilyl trifluoromethanesulfonate, titanium tetrachloride and the like, and boron trifluoride ether complex is preferable. The usage-amount of a Lewis acid is 1 equivalent-5 equivalent normally with respect to a polyvalent iodine compound, Preferably it is 2 equivalent-3 equivalent.

  Any solvent may be used as long as it does not inhibit the reaction. For example, halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane; 2,2,2-trifluoroethanol; benzene; toluene; A mixed solvent is mentioned. The amount of the solvent to be used is in the range of 50 to 100 L with respect to 1 mol of compound (IX).

  The reaction temperature is usually −78 ° C. to 0 ° C., but −50 ° C. to −30 ° C. is preferable. The reaction time is usually 1 to 3 hours, although it depends on the reagents used and the reaction temperature.

7). Step (7)
Step (7) is a method for producing compound (XI) that oxidizes compound (X).
Specifically, it can be carried out by mixing compound (X) and an oxidizing agent in a solvent. The order of adding each sample is not particularly limited.

  Examples of the oxidizing agent include 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), iodine, palladium carbon, chloranil, selenium dioxide and the like, and DDQ is preferable. The amount of the oxidizing agent to be used is generally 1 equivalent to 3 equivalents, preferably 1 equivalent to 1.2 equivalents, relative to compound (X). If the amount is less than this range, the reaction is difficult to proceed.

  The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane; benzene; The usage-amount of a solvent is the range of 50-150L with respect to 1 mol of compounds (X).

The reaction temperature is usually 20 ° C to 100 ° C, preferably 40 ° C to 60 ° C. The reaction time is usually 20 to 40 hours, although it depends on the reagents used and the reaction temperature.
8). Step (8)
Step (8) is a method for producing compound (XII) in which P ² of compound (XI) is selectively deprotected. Step (8), in combination P ¹ and P ² satisfying the above conditions (1), if the reaction conditions that can selectively deprotected only P ^2, can be carried out without any particular limitation.
Specifically, Protective Groups in Organic Synthesis 3rd edition , Wiley, John & Sons, Incorporated (1999) Chapter 3 deprotection methods of P ² described or cited in the like.
Here, deprotection of a benzyl group, which is a representative protecting group, will be described, but step (8) is not limited to the deprotection method.

  The deprotection of the benzyl group can be performed by catalytic reduction, for example, by mixing the compound (XI) and the catalyst in a solvent under a hydrogen gas atmosphere. The order of adding each sample is not particularly limited.

  Examples of the catalyst include palladium carbon, palladium black, palladium hydroxide carbon and the like, and palladium carbon and palladium hydroxide carbon are preferable. The amount of the catalyst to be used is generally 5% to 25% by weight, preferably 10% to 20% by weight, relative to compound (XI). If the amount is less than this range, the reaction is difficult to proceed.

  Any solvent may be used as long as it does not inhibit the reaction. For example, alcohol solvents such as methanol, ethanol, propanol and isopropanol; tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, methyl tert-butyl ether, 1,4-dioxane Ether solvents such as ethyl acetate; water alone or a mixed solvent. The usage-amount of a solvent is the range of 10-100L with respect to 1 mol of compounds (XI).

  The hydrogen atmosphere may be pressurized or normal pressure.

  The reaction temperature is usually 10 ° C to 50 ° C, preferably 20 ° C to 25 ° C. The reaction time is usually 1 hour to 10 hours, although it depends on the reagent used and the reaction temperature.

9. Step (9)
Step (9) is a method for producing compound (XIV) in which compound (XII) and compound (XIII) are reacted. Specifically, it can be carried out by mixing compound (XII), compound (XIII) and a base in a solvent. The order of adding each sample is not particularly limited.

  Compound (XIII) can be synthesized by the method described in Hedayatullah, M .; Leveque, J.C .; Denivelle, L. C.R. Acad. Sci. Paris, Serie C, 1971, 273, 1444-1447. The amount of compound (XIII) to be used is generally 1 equivalent to 5 equivalents, preferably 1.5 equivalents to 2 equivalents, relative to compound (XII). If it exceeds this range, the cost becomes high.

Examples of the base used in the step (9) include triethylamine, pyridine, diisopropylethylamine, N, N-dimethylaniline, 4- (dimethylamino) pyridine, 1,4-diazabicyclo [2.2.2] octane and the like. And triethylamine, pyridine and diisopropylethylamine are preferred. The amount of the base to be used is generally 1 equivalent to 5 equivalents, preferably 1.5 equivalents to 3 equivalents, relative to compound (XII). If it is less than this range, the reaction is difficult to proceed, and if it is more, the cost becomes high.
It is preferable to add more 4- (dimethylamino) pyridine in order to accelerate the reaction. The amount of 4- (dimethylamino) pyridine to be used is generally 0.1 equivalent to 2 equivalents, preferably 0.5 equivalent to 1.1 equivalents, relative to compound (XII).

  The solvent used in step (9) is not particularly limited as long as it does not inhibit the reaction. For example, halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane; tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane. , Methyl tert-butyl ether, ether solvents such as 1,4-dioxane; benzene; toluene alone or a mixed solvent. The usage-amount of a solvent is the range of 1-10L with respect to 1 mol of compounds (XII).

  Although the reaction temperature of a process (9) is 0 degreeC-50 degreeC normally, 20 to 25 degreeC is preferable. The reaction time is usually 1 hour to 5 hours, although it depends on the reagents used and the reaction temperature.

10. Step (10)
Step (10) is a method for producing compound (XV) in which P ¹ of compound (XIV) is selectively deprotected. Step (10) can be carried out without particular limitation as long as it is a reaction condition that can selectively deprotect only P ^{1 in} the combination of P ¹ and P ⁴ satisfying the above condition (3).
Specifically, Protective Groups in Organic Synthesis 3rd edition , Wiley, John & Sons, Incorporated (1999) Chapter 3 Deprotection Method P ¹ described or cited in the like.
Here, deprotection of an isopropyl group, which is a representative protecting group, will be described, but the step (10) is not limited to the deprotection method.

  Deprotection of the isopropyl group can be performed, for example, by mixing compound (XIV) and a Lewis acid in a solvent. The order of adding each sample is not particularly limited.

  Examples of the Lewis acid include boron trichloride, aluminum chloride, aluminum iodide, boron tribromide, iodotrimethylsilane, and the like, and boron trichloride and aluminum iodide are preferable. The amount of the Lewis acid to be used is generally 1 equivalent to 5 equivalents, preferably 2 equivalents to 3 equivalents, relative to compound (XIV). If the amount is less than this range, the reaction does not proceed easily, and if the amount is more than this range, the cost increases.

  The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane; benzene; The usage-amount of a solvent is the range of 10-50L with respect to 1 mol of compounds (XIV).

  The reaction temperature is usually -78 ° C to 25 ° C, preferably -78 ° C to 0 ° C. The reaction time is usually 2 hours to 5 hours, although it depends on the reagents used and the reaction temperature.

11. Step (11)
Step (11) is a method for producing compound (I) in which P ⁴ of compound (XV) is deprotected. Step (11) can be performed without particular limitation as long as the reaction conditions are such that P ⁴ can be deprotected in the combination of P ¹ and P ⁴ satisfying the above condition (3).
Here, deprotection of a 2,2,2-trichloroethyl group, which is a typical protecting group, will be described, but the step (11) is not limited to the deprotection method.

  Deprotection of the 2,2,2-trichloroethyl group can be carried out, for example, by mixing compound (XV), zinc and ammonium salt in a solvent. The order of adding each sample is not particularly limited.

  The amount of zinc to be used is generally 2 equivalents to 5 equivalents, preferably 2.5 equivalents to 3.5 equivalents, relative to compound (XV). If the amount is less than this range, the reaction is difficult to proceed.

  Examples of ammonium salts include ammonium formate and ammonium acetate, with ammonium formate being preferred. The amount of the ammonium salt to be used is generally 1 equivalent to 10 equivalents, preferably 5 equivalents to 7 equivalents, relative to compound (XV).

  Any solvent may be used as long as it does not inhibit the reaction. For example, alcohol solvents such as methanol, ethanol, propanol and isopropanol; tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, methyl tert-butyl ether, 1,4-dioxane Ether solvents such as N; N-dimethylformamide; water alone or a mixed solvent. The usage-amount of a solvent is the range of 50-200L with respect to 1 mol of compounds (XV).

  The reaction temperature is usually from 0 ° C to 50 ° C, but preferably from 20 ° C to 25 ° C. The reaction time is usually 3 hours to 5 hours, although it depends on the reagents used and the reaction temperature.

  By the deprotection method, an ammonium salt of compound (I) is obtained. The ammonium salt of compound (I) can be converted into salts of various bases by conventional methods. For example, it can be converted into a sodium salt by treatment with a sodium type basic ion exchange resin (for example, Amberlite IRS-50).

Compound (IV) obtained by the step (1) is a novel compound and is useful as a synthetic intermediate for lamellarin α20- sulfate or its analog.
As compound (IV), A ring and B ring may each independently have 1 to 3 substituents selected from an alkoxy group, an optionally halogenated alkyl group and a halogen atom, An embodiment in which X ¹ is a trifluoromethanesulfonyloxy group and P ¹ is an isopropyl group is preferred.

The compound (VI) obtained by the step (2) is a novel compound and is useful as a synthetic intermediate for lamellarin α20- sulfate or its analog.
As compound (VI), A ring, B ring and C ring each independently have 1 to 3 substituents selected from an alkoxy group, an optionally halogenated alkyl group and a halogen atom. An embodiment in which P ¹ is an isopropyl group, P ² is a benzyl group, and P ³ is a methoxymethyl group is preferable.

  General formula (VII ') obtained by steps (3) to (5)

(In the formula, A ring, B ring and C ring may each independently have a substituent, and R ⁴ is a hydrogen atom, a carboxyl group or —CO ₂ R ¹ (where R ¹ is halogenated) A lower alkyl group which may be substituted, an aryl group which may have a substituent or an aralkyl group which may have a substituent.), P ¹ represents a hydroxyl protecting group, and P ² represents P ¹ represents a deprotected hydroxyl group capable of protecting groups under conditions that are not deprotected.) the compound represented by is a novel compound useful as a synthetic intermediate for Ramerarin α20- sulfate or an analogue thereof.
As compound (VII ′), ring A, ring B and ring C each independently have 1 to 3 substituents selected from an alkoxy group, an optionally halogenated alkyl group and a halogen atom. An embodiment in which P ¹ is an isopropyl group and P ² is a benzyl group is preferable.

  General formula (I ') obtained by steps (6) to (10)

(In the formula, A ring, B ring and C ring may independently have a substituent, - - - - represents a single bond or a double bond, P 1 ^'is a hydrogen atom or a hydroxyl protecting group P ^{2 ′} is a hydrogen atom, a hydroxyl protecting group deprotectable under conditions where P ^{1 ′} is not deprotected, or —SO ₃ P ⁴ (where P ⁴ is deprotected under conditions where P ^{1 ′} is deprotected). Represents a non- protected sulfonic acid protecting group.), Except that P ^{1 ′} and P ^{2 ′} are simultaneously a hydrogen atom.) Is a novel compound and is a lamellarin α20- sulfate or its They are useful as synthetic intermediates of analogs, integrase inhibitors or antiretroviral agents.

As compound (I ′), A ring, B ring and C ring each independently have 1 to 3 substituents selected from an alkoxy group, an optionally halogenated alkyl group and a halogen atom. An embodiment in which P ^{1 ′} is an isopropyl group and P ^{2 ′} is a hydrogen atom, a benzyl group or a 2,2,2-trichloroethoxysulfonyl group, or A ring, B ring and C ring are each independently 1 to 3 substituents selected from an alkoxy group, an optionally halogenated alkyl group and a halogen atom, P ^{1 ′} is a hydrogen atom, P ^{2 ′} is 2,2 , 2-trichloroethoxysulfonyl group is preferred.

  The pharmaceutically acceptable salt of compound (I ′) may be any salt that forms a non-toxic salt with compound (I ′), such as hydrochloride, sulfate, phosphate, bromide. Inorganic acid salts such as hydrates; or oxalate, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, gluconic acid Organic salts such as salts, ascorbates, methylsulfonates, benzylsulfonates; or inorganic base salts such as sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts; or methylamine salts, diethylamine salts, Organic base salts such as triethylamine salt, triethanolamine salt, ethylenediamine salt, tris (hydroxymethyl) methylamine salt, guanidine salt, choline salt, cinchonine salt; or Jin salts, amino acid salts such as arginine salt. Moreover, the hydrate or solvate of compound (I ') is also included.

Compound (I ′) is administered to mammals (human, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, etc.) as an inhibitor of integrase, which is an essential enzyme for retrovirus growth. be able to.
Examples of retroviruses to be prevented or treated according to the present invention include human immunodeficiency virus (HIV), human T cell lymphocyte lymphocyte-1 (HTLV-1), and the like. Therefore, the compound (I ′) of the present invention can be used for diseases caused by these retroviruses such as acquired immune deficiency syndrome (AIDS), HTLV-1 associated myelopathy (HAM), etc. It is useful as a preventive / therapeutic agent.

When the compound is used as a pharmaceutical preparation, a pharmaceutically acceptable carrier, excipient, diluent, extender, disintegrant, stabilizer, preservative, buffer, emulsifier, fragrance, coloring agent, which is generally known per se, Sweeteners, thickeners, flavoring agents, solubilizing agents, other additives, specifically water, vegetable oils, alcohols such as ethanol or benzyl alcohol, polyethylene glycol, glycerol triacetate, gelatin, lactose, starch and other carbohydrates, stearin Mixed with magnesium acid, talc, lanolin, petrolatum, etc., in a conventional manner, tablets, pills, powders, granules, suppositories, injections, eye drops, solutions, capsules, troches, aerosols, elixirs, suspensions By taking the form of a suspension, emulsion, syrup, etc., it can be administered systemically or locally, orally or parenterally.
The dosage varies depending on age, body weight, symptoms, therapeutic effects, administration method, etc., but is usually in the range of 0.01 mg to 1 g per adult, once or several times a day, orally or intravenously. It is administered in a dosage form such as an injection.

  Hereinafter, the present invention will be described more specifically with reference to examples shown in the following schemes. The present invention is not limited by these.

  The compound numbers in the following production examples and examples correspond to the numbers in the above schemes, and (a) to (n) correspond to the symbols on the arrows in the above schemes.

Production Example 1
(A) Synthesis of Compound 2:
Two mixtures of 2- (3,4-dimethoxyphenyl) ethylamine (10.0 g, 55 mmol), methyl bromoacetate (33.3 g, 110 mmol), sodium bicarbonate (33.3 g, 390 mmol) and acetonitrile (150 mL) Stir to reflux for 5 hours. After standing to cool, the insoluble material was filtered off with suction, and the solvent was distilled off under reduced pressure. Water was added to the remaining oil and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and dichloromethane was evaporated under reduced pressure. The residue was distilled under reduced pressure to obtain 16.4 g of Compound 2 as a pale yellow oil. Yield 91%. Boiling point 210 ° C / 1mmHg.
¹ H NMR (300 MHz, CDCl ₃ ): δ 2.74 (t, J = 7.8 Hz, 2H), 2.97 (t, J = 7.8 Hz, 2H), 3.60 (s, 4H), 3.71 (s, 6H), 3.85 (s, 3H), 3.87 (s, 3H), 6.72-6.81 (m, 3H).

Production Example 2
(B) Synthesis of Compound 3:
Under an argon atmosphere, dry tetrahydrofuran (25 mL) was added to a mixture of sodium hydride (2.46 g, 61.5 mmol) and dimethyl oxalate (3.63 g, 30.7 mmol) washed with dry hexane, and reflux with stirring was started. A solution of compound 2 (5.00 g, 15.4 mmol) in dry tetrahydrofuran (75 mL) was added dropwise thereto over 1.5 hours, and the mixture was further refluxed with stirring for 3 hours. After allowing to cool, acetic acid (3.5 mL) was added, and the solvent was evaporated under reduced pressure. The residue was poured into ice water, and the pH of the mixture was adjusted to 3 with hydrochloric acid. The resulting solid was collected by suction filtration. After washing with water and drying over anhydrous sodium sulfate, 4.98 g of compound 3 was obtained as a white powder. Yield 85%. Melting point 141-142 ° C. (CH ₂ Cl ₂ / hexane).
¹ H NMR (300 MHz, CDCl ₃ ): δ 2.83 (t, J = 7.3 Hz, 2H), 3.86 (s, 6H), 3.91 (s, 6H), 4.70 (t, J = 7.3 Hz, 2H), 6.58 (d, J = 1.7 Hz, 1H), 6.64 (dd, J = 1.7 and 8.2 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 7.48 (br s, 2H).

Production Example 3
(C) Synthesis of Compound 4:
Trifluoromethanesulfonic anhydride (3.94 mL, 23.3 mmol) was added dropwise to a solution of compound 3 (4.00 g, 10.5 mmol) in dry pyridine (16 mL) at 0 ° C. in an argon atmosphere, and further at the same temperature for 2 hours. Stir. After raising to room temperature, water (20 mL) was added and extracted with ether. The extract was washed successively with 3N HCl, water and saturated brine, and dried over anhydrous sodium sulfate. Ether was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 6.25 g of compound 4 as a white solid. Yield 92%. Melting point 64-65 ° C. (CH ₂ Cl ₂ / hexane).
¹ H NMR (300 MHz, CDCl ₃ ): δ 2.99 (t, J = 7.0 Hz, 2H), 3.85 (s, 3H), 3.85 (s, 3H), 3.87 (s, 6H), 5.09 (t, J = 7.0 Hz, 2H), 6.59-6.62 (m, 2H), 6.75 (d, J = 8.8 Hz, 1H).

Example 1
(D) Synthesis of Compound 6:
A mixture of compound 4 (6.43 g, 10.0 mmol), arylboronic acid 5 (2.10 g, 10.0 mmol) and Pd (PPh ₃ ) ₄ (231 mg, 0.20 mmol) was replaced with argon by vacuum degassing. Tetrahydrofuran (200 mL) was added to this solid mixture and dissolved by stirring. Further, an aqueous sodium carbonate solution [Na ₂ CO ₃ (7.00 g, 66.0 mmol) + water (20 mL)] degassed with argon was added. The mixture was refluxed for 5 hours. The solvent was depressurizingly distilled after standing_to_cool. Water was added to the residue and extracted with dichloromethane. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (toluene: ethyl acetate = 8: 1) to obtain 5.26 g of compound 6 as a white solid. Yield 80%. Melting point 88.5-90 ° C. (ether / hexane mixed solvent).
¹ H NMR (300 MHz, CDCl ₃ ): δ 1.36 (d, J = 6.1 Hz, 6H), 3.04 (t, J = 7.3 Hz, 2H), 3.57 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 3.89 (s, 3H), 3.91 (s, 3H), 4.41-4.55 (m, 1H), 4.96 (t, J = 7.3 Hz, 2H), 6.69 (d, J = 1.8 Hz , 1H), 6.72 (dd, J = 1.8 and 8.1 Hz, 1H), 6.76-6.82 (m, 3H), 6.87 (d, J = 8.8 Hz, 1H).

Example 2
(E) Synthesis of Compound 8:
A mixture of compound 6 (4.33 g, 6.57 mmol), arylboronic acid 7 (4.18 g, 13.1 mmol) and Pd (PPh ₃ ) ₄ (607 mg, 0.526 mmol) was replaced with argon by vacuum degassing. Tetrahydrofuran (66 mL) was added to this solid mixture and dissolved by stirring. Further, an aqueous sodium carbonate solution [Na ₂ CO ₃ (4.60 g, 43.4 mmol) + water (13 mL)] degassed with argon was added. The mixture was refluxed for 20 hours. The solvent was depressurizingly distilled after standing_to_cool. Water was added to the residue and extracted with dichloromethane. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane) to obtain 4.62 g of compound 6 as a pale yellow solid. Yield 90%. Melting point: 102.5-104 ° C. (dichloromethane / hexane mixed solvent).
¹ H NMR (300 MHz, CDCl ₃ ): δ 1.16 (d, J = 5.4 Hz, 6H), 3.09 (t, J = 7.4 Hz, 2H), 3.22 (s, 3H), 3.54 (s, 6H), 3.59 (s, 3H), 3.81 (s, 3H), 3.86 (s, 3H), 3.89 (s, 3H), 4.16-4.29 (m, 1H), 4.72 (br s, 2H), 4.88 (br s, 2H), 5.08 (s, 2H), 6.34 (s, 1H), 6.57 (d, J = 1.7 Hz, 1H), 6.62 (dd, J = 1.9 and 8.2 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.72 (s, 1H), 6.76-6.86 (m, 3H), 7.25-7.46 (m, 5H).

Example 3
(F) Synthesis of Compound 9:
A mixed solution of Compound 8 (3.085 g, 3.94 mmol), methanol (79 mL) and concentrated hydrochloric acid (7.9 mL) was stirred and refluxed for 2 hours. Water (80 mL) was added, and the mixture was concentrated under reduced pressure and extracted with dichloromethane. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 20: 1) to obtain 2.578 g of compound 9 as a white solid. Yield 93%. Melting point 98.5-101 ° C (dichloromethane / hexane mixed solvent).
¹ H NMR (300 MHz, CDCl ₃ ): δ 1.35 (d, J = 5.6 Hz, 3H), 1.37 (d, J = 5.6 Hz, 3H), 3.09 (t, J = 7.6 Hz, 2H), 3.44 ( s, 3H), 3.57 (s, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 3.92 (s, 3H), 4.45-4.59 (m, 1H), 5.10 (t, J = 7.6 Hz , 2H), 5.17 (s, 2H), 6.53 (s, 1H), 6.77-6.83 (m, 3H), 6.85-6.90 (m, 3H), 6.98 (d, J = 8.6 Hz, 1H), 7.29- 7.45 (m, 5H).

Example 4
(G) Synthesis of Compound 10:
Under an argon atmosphere, a mixed solution of compound 9 (2.463 g, 3.48 mmol), ethanol (137 mL) and 40% aqueous KOH solution (137 mL) was stirred and refluxed for 3 hours. After allowing to cool, ethanol was distilled off and the pH of the solution was adjusted to 2 with concentrated hydrochloric acid. Then, it extracted with dichloromethane. After drying over anhydrous sodium sulfate, dichloromethane was distilled off. Paratoluenesulfonic acid (331 mg) and dichloromethane (150 mL) were added to the residue, and the solution was refluxed for 1 hour. The reaction solution was washed with water and dried over anhydrous sodium sulfate, and then dichloromethane was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 15: 1) to obtain 1.848 g of compound 10 as a light brown solid. Yield 77%. Melting point 214-215 ° C. (dichloromethane / hexane mixed solvent).
¹ H NMR (300 MHz, CDCl ₃ ): δ 1.34 (d, J = 6.0 Hz, 3H), 1.35 (d, J = 6.0 Hz, 3H), 3.09 (t, J = 7.7 Hz, 2H), 3.43 ( s, 3H), 3.83 (s, 6H), 3.91 (s, 3H), 4.46-4.60 (m, 1H), 5.11-5.19 (m, 4H), 6.46 (s, 1H), 6.77 (s, 2H) , 6.83 (s, 1H), 6.87-6.96 (m, 3H), 7.01 (d, J = 8.0 Hz, 1H), 7.29-7.44 (m, 5H).

Example 5
(H) Synthesis of Compound 11:
Under an argon atmosphere, a mixture of compound 10 (1.582 g, 2.28 mmol), Cu ₂ O (326 mg, 2.28 mmol) and quinoline (25 mL) was heated and stirred for 10 minutes in an oil bath set at 220 ° C. The mixture was allowed to cool, diluted with dichloromethane, and filtered through celite. The filtrate was evaporated to remove dichloromethane. Then quinoline was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 1.418 g of compound 11 as a pale yellow solid. Yield 96%. Melting point 135-136 ° C. (dichloromethane / hexane mixed solvent).
¹ H NMR (300 MHz, CDCl ₃ ): δ 1.37 (d, J = 6.1 Hz, 6H), 3.10 (t, J = 7.0 Hz, 2H), 3.58 (s, 3H), 3.78 (s, 3H), 3.85 (s, 3H), 3.90 (s, 3H), 4.45-4.59 (m, 1H), 4.63 (t, J = 7.0 Hz, 2H), 5.19 (s, 2H), 6.60 (d, J = 1.8 Hz , 1H), 6.68 (dd, J = 1.8 and 8.1 Hz, 1H), 6.74 (s, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.90-6.97 (m, 4H), 7.10 (s, 1H), 7.28-7.47 (m, 5H).

Example 6
(I) Synthesis of Compound 12:
Under an argon atmosphere, Compound 11 (1.000 g, 1.54 mmol) was dissolved in dichloromethane (110 mL) with stirring and cooled to −40 ° C. To this solution was added dropwise a solution of phenyl iodine (III) bis (trifluoroacetate) (794 mg, 1.85 mmol) and BF ₃ · OEt ₂ (468 mL, 3.69 mmol) in dichloromethane (37 mL). After stirring at the same temperature for 1.5 hours, a saturated aqueous ammonium chloride solution was added, and the temperature was returned to room temperature. The reaction solution was washed with water and dried over anhydrous sodium sulfate, and then dichloromethane was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 20: 1) to obtain 0.944 g of compound 12 as a pale yellow solid. Yield 95%. Melting point 209-210 ° C (dichloromethane / diethyl ether mixed solvent).
¹ H NMR (300 MHz, CDCl ₃ ): δ 1.33 (d, J = 6.0 Hz, 3H), 1.35 (d, J = 6.0 Hz, 3H), 3.11 (t, J = 6.7 Hz, 2H), 3.37 ( s, 3H), 3.47 (s, 3H), 3.89 (s, 3H), 3.93 (s, 3H), 4.46-4.60 (m, 1H), 4.68-4.89 (m, 2H), 5.16 (s, 2H) , 6.68 (s, 1H), 6.72 (s, 1H), 6.75 (s, 1H), 6.90 (s, 1H), 7.03-7.20 (m, 3H), 7.28-7.46 (m, 5H).

Example 7
(J) Synthesis of Compound 13:
Under an argon atmosphere, a mixed solution of Compound 12 (893 mg, 1.38 mmol), DDQ (312 mg, 1.38 mmol) and dichloromethane (160 mL) was refluxed for 30 hours. After distilling off dichloromethane under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 20: 1) to obtain 882 mg of compound 13 as a pale yellow solid. Yield 99%. Melting point 208-209 ° C. (dichloromethane / hexane mixed solvent).
¹ H NMR (300 MHz, CDCl ₃ ): δ 1.35 (d, J = 6.0 Hz, 3H), 1.36 (d, J = 6.0 Hz, 3H), 3.47 (s, 3H), 3.49 (s, 3H), 3.96 (s, 3H), 3.98 (s, 3H), 4.48-4.61 (m, 1H), 5.19 (s, 2H), 6.77 (s, 1H), 6.96 (s, 1H), 7.05 (d, J = 7.3 Hz, 1H), 7.08 (s, 1H), 7.12-7.22 (m, 4H), 7.28-7.47 (m, 5H), 9.22 (d, J = 7.3 Hz, 1H).

Example 8
(K) Synthesis of Compound 14:
Under a hydrogen atmosphere (normal pressure), a mixture of compound 13 (500 mg, 0.774 mmol), 10% Pd-C (100 mg) and ethyl acetate (40 mL) was vigorously stirred for 2 hours. The mixture was filtered through celite, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain 424 mg of compound 14 as a pale yellow solid. Yield 99%. Melting point 262.5-263.5 [deg.] C. (dichloromethane / diethyl ether mixed solvent).
¹ H NMR (300 MHz, CDCl ₃ ): δ 1.36 (d, J = 6.0 Hz, 3H), 1.37 (d, J = 6.0 Hz, 3H), 3.48 (s, 3H), 3.51 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 4.49-4.62 (m, 1H), 5.81 (s, 1H), 6.72 (s, 1H), 7.02 (s, 1H), 7.05 (d, J = 7.3 Hz, 1H), 7.09 (s, 1H), 7.12-7.23 (m, 4H), 9.24 (d, J = 7.3 Hz, 1H).

Example 9
(L) Synthesis of Compound 15:
Under an argon atmosphere, a mixed solution of compound 14 (224 mg, 0.403 mmol), 4-dimethylaminomethylpyridine (49 mg, 0.403 mmol), triethylamine (112 mL, 0.806 mmol) and tetrahydrofuran (5.0 mL) was added to trichlorochlorosulfate. A solution of ethyl (200 mg, 0.806 mmol) in tetrahydrofuran (2.0 mL) was added dropwise. After stirring at room temperature for 4 hours, water was added to stop the reaction. The solvent was distilled off under reduced pressure, and dichloromethane extraction was performed. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After distilling off dichloromethane, the residue was purified by silica gel column chromatography (solvent: dichloromethane) to obtain 296 mg of Compound 15 as a pale yellow solid. Yield 96%. Melting point: 144-146 ° C. (dichloromethane / hexane mixed solvent).
¹ H NMR (300 MHz, CDCl ₃ ): δ 1.36 (d, J = 6.0 Hz, 3H), 1.37 (d, J = 6.0 Hz, 3H), 3.48 (s, 3H), 3.50 (s, 3H), 3.97 (s, 3H), 4.00 (s, 3H), 4.49-4.64 (m, 1H), 4.91 (d, J = 10.8 Hz, 1H), 4.95 (d, J = 10.8 Hz, 1H), 6.92 (s , 1H), 7.09 (d, J = 7.4 Hz, 1H), 7.10 (s, 1H), 7.13-7.23 (m, 4H), 7.46 (s, 1H), 9.21 (d, J = 7.4 Hz, 1H) .

Example 10
(m) Synthesis of Compound 16:
Under argon atmosphere at −78 ° C., 1M heptane solution of boron trichloride (391 mL, 0.391 mmol) was added dropwise to a solution of compound 15 (100 mg, 0.130 mmol) in dichloromethane (5.0 mL) and stirred for 30 minutes. . Then, it heated up at 0 degreeC and stirred at the same temperature for 4 hours. Water (3.0 mL) and saturated aqueous sodium hydrogen carbonate solution (2 mL) were sequentially added to stop the reaction. Ethyl acetate was added to the reaction solution, and the separated organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off ethyl acetate under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane) to obtain 91 mg of compound 16 as a pale yellow solid. Yield 96%. Melting point 239-240 ° C. (dichloromethane / hexane mixed solvent).
¹ H NMR (300 MHz, CDCl ₃ ): δ 3.50 (s, 3H), 3.52 (s, 3H), 3.99 (s, 3H), 4.01 (s, 3H), 4.94 (s, 2H), 5.86 (s , 1H), 6.95 (s, 1H), 7.07-7.16 (m, 4H), 7.19 (s, 1H), 7.21 (d, J = 1.6 Hz, 1H), 7.47 (s, 1H), 9.21 (d, J = 7.4 Hz, 1H).

Example 11
(N) Synthesis of compound 17 (lamellarin α 20-sulfate):
A mixture of Compound 16 (50 mg, 0.069 mmol), ammonium formate (26 mg, 0.414 mmol), zinc dust (14 mg, 0.207 mg atom), tetrahydrofuran (5.0 mL) and methanol (5.0 mL) at room temperature for 4 hours. Stir. Celite filtration was performed, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain the target ammonium salt. This ammonium salt was passed through a column of ion exchange resin Amberlite IRS-50 (Na ⁺ type) (methanol) and converted to a sodium salt. The crude compound 17 thus obtained was passed through a Sephadex LH-20 column (dichloromethane: methanol = 1: 1) to obtain 34 mg of pure compound 17 (lamellarin α20-sulfate) as a pale yellow solid. . Yield 80%. Melting point: 263-269 ° C. (decomposition, unrecrystallized).
IR (KBr): 3448, 1695, 1487, 1419, 1272, 1223, 1167, 1048, 839 cm ^-1 ;
¹ H NMR (400 MHz, DMSO-d ₆ , 17 mg / 0.7 mL): δ 3.37 (s, 3H), 3.37 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 6.80 (s , 1H), 6.94 (dd, J = 2.0 and 8.0 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 7.18 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 7.4 Hz, 1H), 7.38 (s, 1H), 7.57 (s, 1H), 8.48 (br s, 1H), 9.03 (d, J = 7.4 Hz, 1H);
¹³ C NMR (100 MHz, DMSO-d ₆ , 17 mg / 0.7 mL): δ 54.36, 54.96, 55.48, 55.97, 104.63, 105.64, 106.80, 108.00, 108.66, 111.13, 111.40, 112.70, 113.42, 118.00, 118.05, 121.36 , 121.88, 124.09, 126.83, 127.80, 133.26, 143.00, 144.93, 146.48, 147.87, 147.99, 148.71, 149.71, 153.96.
HRFABMS m / z.Calcd for C ₂₉ H ₂₃ NNaO ₁₁ S [(M + H) ⁺ ]: 616.0890. Found: 616.0889.
HRFABMS m / z.Calcd for C ₂₉ H ₂₂ NO ₁₁ S [(M-Na) ^- ]: 592.0914. Found: 592.0913.

Since the method of the present invention is a practical method with high flexibility of lamellarin α20- sulfate or its analog, it is suitable for large-scale preparation of lamellarin α20- sulfate or the synthesis of its analog. Therefore, it is an excellent method applicable to the development of new anti-HIV agents.

Claims (30)

Formula (IV)

(In the formula, the A ring and the B ring may each independently have a substituent, and R ¹ may be a halogenated lower alkyl group, an optionally substituted aryl group, or a substituted group. An aralkyl group which may have a group, X ¹ represents a halogen atom, a trifluoromethanesulfonyloxy group or an arylsulfonyloxy group which may have a substituent, and P ¹ represents a hydroxyl protecting group. And a compound represented by the general formula (V)

(In the formula, ring C may have a substituent, and R ³ represents a hydrogen atom, a lower alkyl group which may be halogenated, or may be bonded to each other to form a ring. P ² represents a hydroxyl protecting group that can be deprotected under conditions where P ¹ is not deprotected, and P ³ represents a hydroxyl protecting group that can be deprotected under conditions where P ¹ and P ² are not deprotected. A compound represented by the general formula (VI), characterized by reacting a compound in the presence of a transition metal catalyst

(Wherein each symbol is as defined above) (wherein P ¹ , P ² and P ³ are a methoxymethyl group, a benzyloxymethyl group, a methoxyethoxymethyl group, 2- (trimethylsilyl) ethoxymethyl group, methylthiomethyl group, phenylthiomethyl group, 2,2-dichloro-1,1-difluoroethyl group, tetrahydropyranyl group, phenacyl group, p-bromophenacyl group, cyclopropylmethyl group, Allyl group, isopropyl group, cyclohexyl group, tert-butyl group, benzyl group, 2,6-dimethylbenzyl group, 4-methoxybenzyl group, o-nitrobenzyl group, 2,6-dichlorobenzyl group, 4- (dimethylamino) Carbonyl) benzyl, 9-anthrylmethyl, 4-picolyl, heptafluoro-p-tri Group, tetrafluoro-4-pyridyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, acetyl group, levulinoyl group, pivaloyl group, benzoyl group, 9-fluorenecarbonyl group, methoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, dimethylphosphonyl group, dimethylthiophosphonyl group, methanesulfonyl group, and p-toluenesulfonyl group) . The production method according to claim 1, wherein P ¹ is an isopropyl group, P ² is a benzyl group, and P ³ is a methoxymethyl group. General formula (VI)

(In the formula, A ring, B ring and C ring may each independently have a substituent, and R ¹ may be a halogenated lower alkyl group or a substituent aryl. An aralkyl group which may have a group or a substituent, P ¹ represents a hydroxyl protecting group, P ² represents a hydroxyl protecting group which can be deprotected under the condition that P ¹ is not deprotected, and P ³ represents P ¹ and P ² represent a hydroxyl-protecting group that can be deprotected under the condition that is not deprotected.) P ³ of the compound represented by the above is selectively deprotected, and transesterification is performed in the molecule to form a lactone ring. The general formula (VII)

(Wherein each symbol is as defined above) (wherein P ¹ , P ² and P ³ are a methoxymethyl group, a benzyloxymethyl group, a methoxyethoxymethyl group, 2- (trimethylsilyl) ethoxymethyl group, methylthiomethyl group, phenylthiomethyl group, 2,2-dichloro-1,1-difluoroethyl group, tetrahydropyranyl group, phenacyl group, p-bromophenacyl group, cyclopropylmethyl group, Allyl group, isopropyl group, cyclohexyl group, tert-butyl group, benzyl group, 2,6-dimethylbenzyl group, 4-methoxybenzyl group, o-nitrobenzyl group, 2,6-dichlorobenzyl group, 4- (dimethylamino) Carbonyl) benzyl, 9-anthrylmethyl, 4-picolyl, heptafluoro-p-tri Group, tetrafluoro-4-pyridyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, acetyl group, levulinoyl group, pivaloyl group, benzoyl group, 9-fluorenecarbonyl group, methoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, dimethylphosphonyl group, dimethylthiophosphonyl group, methanesulfonyl group, and p-toluenesulfonyl group) . The production method according to claim 3, wherein P ¹ is an isopropyl group, P ² is a benzyl group, and P ³ is a methoxymethyl group. Formula (VII)

(In the formula, A ring, B ring and C ring may each independently have a substituent, and R ¹ may be a halogenated lower alkyl group or a substituent aryl. An aralkyl group which may have a group or a substituent, P ¹ represents a hydroxyl protecting group, and P ² represents a hydroxyl protecting group which can be deprotected under the condition that P ¹ is not deprotected). A compound having the general formula (VIII)

(Wherein each symbol has the same meaning as described above) (wherein P ¹ and P ² are a methoxymethyl group, a benzyloxymethyl group, a methoxyethoxymethyl group, 2- ( Trimethylsilyl) ethoxymethyl group, methylthiomethyl group, phenylthiomethyl group, 2,2-dichloro-1,1-difluoroethyl group, tetrahydropyranyl group, phenacyl group, p-bromophenacyl group, cyclopropylmethyl group, allyl group, Isopropyl group, cyclohexyl group, tert-butyl group, benzyl group, 2,6-dimethylbenzyl group, 4-methoxybenzyl group, o-nitrobenzyl group, 2,6-dichlorobenzyl group, 4- (dimethylaminocarbonyl) benzyl Group, 9-anthrylmethyl group, 4-picolyl group, heptafluoro-p-tolyl group, Trifluoro-4-pyridyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, acetyl group, levulinoyl group, pivaloyl group, benzoyl group, 9-fluorenecarbonyl group, methoxycarbonyl group, 2,2 , 2-trichloroethoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, dimethylphosphonyl group, dimethylthiophosphonyl group, methanesulfonyl group, and p-toluenesulfonyl group . P ¹ is an isopropyl group, P ² is benzyl group, The process according to claim 5, wherein. Formula (VIII)

(In the formula, A ring, B ring and C ring may each independently have a substituent, P ¹ represents a hydroxyl protecting group, and P ² can be deprotected under the condition that P ¹ is not deprotected. A compound represented by formula (IX), wherein the compound represented by formula (IX) is decarboxylated.

(Wherein each symbol has the same meaning as described above) (wherein P ¹ and P ² are a methoxymethyl group, a benzyloxymethyl group, a methoxyethoxymethyl group, 2- ( Trimethylsilyl) ethoxymethyl group, methylthiomethyl group, phenylthiomethyl group, 2,2-dichloro-1,1-difluoroethyl group, tetrahydropyranyl group, phenacyl group, p-bromophenacyl group, cyclopropylmethyl group, allyl group, Isopropyl group, cyclohexyl group, tert-butyl group, benzyl group, 2,6-dimethylbenzyl group, 4-methoxybenzyl group, o-nitrobenzyl group, 2,6-dichlorobenzyl group, 4- (dimethylaminocarbonyl) benzyl Group, 9-anthrylmethyl group, 4-picolyl group, heptafluoro-p-tolyl group, Trifluoro-4-pyridyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, acetyl group, levulinoyl group, pivaloyl group, benzoyl group, 9-fluorenecarbonyl group, methoxycarbonyl group, 2,2 , 2-trichloroethoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, dimethylphosphonyl group, dimethylthiophosphonyl group, methanesulfonyl group, and p-toluenesulfonyl group . P ¹ is an isopropyl group, P ² is benzyl group, the manufacturing method according to claim 7 wherein. General formula (IX)

(In the formula, A ring, B ring and C ring may each independently have a substituent, P ¹ represents a hydroxyl protecting group, and P ² can be deprotected under the condition that P ¹ is not deprotected. A compound represented by formula (X), wherein the compound represented by formula (X) represents a hydroxyl protecting group.

(Wherein each symbol has the same meaning as described above) (wherein P ¹ and P ² are a methoxymethyl group, a benzyloxymethyl group, a methoxyethoxymethyl group, 2- ( Trimethylsilyl) ethoxymethyl group, methylthiomethyl group, phenylthiomethyl group, 2,2-dichloro-1,1-difluoroethyl group, tetrahydropyranyl group, phenacyl group, p-bromophenacyl group, cyclopropylmethyl group, allyl group, Isopropyl group, cyclohexyl group, tert-butyl group, benzyl group, 2,6-dimethylbenzyl group, 4-methoxybenzyl group, o-nitrobenzyl group, 2,6-dichlorobenzyl group, 4- (dimethylaminocarbonyl) benzyl Group, 9-anthrylmethyl group, 4-picolyl group, heptafluoro-p-tolyl group, Trifluoro-4-pyridyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, acetyl group, levulinoyl group, pivaloyl group, benzoyl group, 9-fluorenecarbonyl group, methoxycarbonyl group, 2,2 , 2-trichloroethoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, dimethylphosphonyl group, dimethylthiophosphonyl group, methanesulfonyl group, and p-toluenesulfonyl group . P ¹ is an isopropyl group, P ² is benzyl group, The method according to claim 9, wherein. Formula (X)

(In the formula, A ring, B ring and C ring may each independently have a substituent, P ¹ represents a hydroxyl protecting group, and P ² can be deprotected under the condition that P ¹ is not deprotected. A compound represented by formula (XI), wherein the compound represented by formula (XI) is oxidized.

(Wherein each symbol has the same meaning as described above) (wherein P ¹ and P ² are a methoxymethyl group, a benzyloxymethyl group, a methoxyethoxymethyl group, 2- ( Trimethylsilyl) ethoxymethyl group, methylthiomethyl group, phenylthiomethyl group, 2,2-dichloro-1,1-difluoroethyl group, tetrahydropyranyl group, phenacyl group, p-bromophenacyl group, cyclopropylmethyl group, allyl group, Isopropyl group, cyclohexyl group, tert-butyl group, benzyl group, 2,6-dimethylbenzyl group, 4-methoxybenzyl group, o-nitrobenzyl group, 2,6-dichlorobenzyl group, 4- (dimethylaminocarbonyl) benzyl Group, 9-anthrylmethyl group, 4-picolyl group, heptafluoro-p-tolyl group, Trifluoro-4-pyridyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, acetyl group, levulinoyl group, pivaloyl group, benzoyl group, 9-fluorenecarbonyl group, methoxycarbonyl group, 2,2 , 2-trichloroethoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, dimethylphosphonyl group, dimethylthiophosphonyl group, methanesulfonyl group, and p-toluenesulfonyl group . P ¹ is an isopropyl group, P ² is benzyl group, The method of claim 11, wherein. General formula (XI)

(In the formula, A ring, B ring and C ring may each independently have a substituent, P ¹ represents a hydroxyl protecting group, and P ² can be deprotected under the condition that P ¹ is not deprotected. Wherein P ² of the compound represented by the formula (XII) is selectively deprotected.

(Wherein each symbol has the same meaning as described above) (wherein P ¹ and P ² are a methoxymethyl group, a benzyloxymethyl group, a methoxyethoxymethyl group, 2- ( Trimethylsilyl) ethoxymethyl group, methylthiomethyl group, phenylthiomethyl group, 2,2-dichloro-1,1-difluoroethyl group, tetrahydropyranyl group, phenacyl group, p-bromophenacyl group, cyclopropylmethyl group, allyl group, Isopropyl group, cyclohexyl group, tert-butyl group, benzyl group, 2,6-dimethylbenzyl group, 4-methoxybenzyl group, o-nitrobenzyl group, 2,6-dichlorobenzyl group, 4- (dimethylaminocarbonyl) benzyl Group, 9-anthrylmethyl group, 4-picolyl group, heptafluoro-p-tolyl group, Trifluoro-4-pyridyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, acetyl group, levulinoyl group, pivaloyl group, benzoyl group, 9-fluorenecarbonyl group, methoxycarbonyl group, 2,2 , 2-trichloroethoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, dimethylphosphonyl group, dimethylthiophosphonyl group, methanesulfonyl group, and p-toluenesulfonyl group . The production method according to claim 13, wherein P ¹ is an isopropyl group and P ² is a benzyl group. General formula (XII)

(Wherein the A ring, the B ring and the C ring may each independently have a substituent, and P ¹ represents a hydroxyl protecting group), a compound represented by the general formula (XIII)

(Wherein P ⁴ represents a sulfonic acid protecting group that is not deprotected under the condition that P ¹ is deprotected), and is reacted with a compound represented by the general formula (XIV)

(Wherein each symbol has the same meaning as described above) (wherein P ¹ is a methoxymethyl group, benzyloxymethyl group, methoxyethoxymethyl group, 2- (trimethylsilyl) ethoxy) Methyl group, methylthiomethyl group, phenylthiomethyl group, 2,2-dichloro-1,1-difluoroethyl group, tetrahydropyranyl group, phenacyl group, p-bromophenacyl group, cyclopropylmethyl group, allyl group, isopropyl group, Cyclohexyl group, tert-butyl group, benzyl group, 2,6-dimethylbenzyl group, 4-methoxybenzyl group, o-nitrobenzyl group, 2,6-dichlorobenzyl group, 4- (dimethylaminocarbonyl) benzyl group, 9 -Anthrylmethyl group, 4-picolyl group, heptafluoro-p-tolyl group, tetrafur Oro-4-pyridyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, acetyl group, levulinoyl group, pivaloyl group, benzoyl group, 9-fluorenecarbonyl group, methoxycarbonyl group, 2,2, 2-trichloroethoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, dimethylphosphonyl group, dimethylthiophosphonyl group, methanesulfonyl group, and p-toluenesulfonyl group, and P ⁴ is 2,2, Selected from 2-trichloroethyl group and 2- (trimethylsilyl) ethyl group) . The production method according to claim 15, wherein P ¹ is an isopropyl group and P ⁴ is a 2,2,2-trichloroethyl group. General formula (XIV)

(In the formula, A ring, B ring, and C ring may each independently have a substituent, P ¹ represents a hydroxyl protecting group, and P ⁴ is not deprotected under the condition that P ¹ is deprotected. A sulfonic acid protecting group), wherein P ¹ of the compound represented by formula (XV) is selectively deprotected.

(Wherein each symbol has the same meaning as described above) (wherein P ¹ is a methoxymethyl group, benzyloxymethyl group, methoxyethoxymethyl group, 2- (trimethylsilyl) ethoxy) Methyl group, methylthiomethyl group, phenylthiomethyl group, 2,2-dichloro-1,1-difluoroethyl group, tetrahydropyranyl group, phenacyl group, p-bromophenacyl group, cyclopropylmethyl group, allyl group, isopropyl group, Cyclohexyl group, tert-butyl group, benzyl group, 2,6-dimethylbenzyl group, 4-methoxybenzyl group, o-nitrobenzyl group, 2,6-dichlorobenzyl group, 4- (dimethylaminocarbonyl) benzyl group, 9 -Anthrylmethyl group, 4-picolyl group, heptafluoro-p-tolyl group, tetrafur Oro-4-pyridyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, acetyl group, levulinoyl group, pivaloyl group, benzoyl group, 9-fluorenecarbonyl group, methoxycarbonyl group, 2,2, 2-trichloroethoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, dimethylphosphonyl group, dimethylthiophosphonyl group, methanesulfonyl group, and p-toluenesulfonyl group, and P ⁴ is 2,2, Selected from 2-trichloroethyl group and 2- (trimethylsilyl) ethyl group) . The production method according to claim 17, wherein P ¹ is an isopropyl group and P ⁴ is a 2,2,2-trichloroethyl group. General formula (XV)

(Wherein A ring, B ring and C ring may each independently have a substituent, and P ⁴ represents a sulfonic acid protecting group). Deprotecting P ⁴ of the compound represented by The general formula (I)

(Wherein each symbol is as defined above) or a method for producing a salt thereof (wherein P ⁴ is a 2,2,2-trichloroethyl group and a 2- (trimethylsilyl) ethyl group). Selected from.) The production method according to claim 19, wherein P ⁴ is a 2,2,2-trichloroethyl group. General formula (I), characterized in that it comprises at least one method selected from the production methods according to claims 1, 3, 5, 7, 9, 11, 13, 15, 17 and 19.

(Wherein the A ring, the B ring and the C ring may each independently have a substituent), or a method for producing a salt thereof. A process according to claim 1, 3, 5, 7, 9, 11, 13, 15, 17 and 19, characterized in that it comprises the general formula (I)

(Wherein the A ring, the B ring and the C ring may each independently have a substituent), or a method for producing a salt thereof. General formula (VI)

(In the formula, A ring, B ring and C ring may each independently have a substituent, and R ¹ may be a halogenated lower alkyl group or a substituent aryl. An aralkyl group which may have a group or a substituent, P ¹ represents a hydroxyl protecting group, P ² represents a hydroxyl protecting group which can be deprotected under the condition that P ¹ is not deprotected, and P ³ represents P ¹ and P ² indicates the deprotected hydroxyl group capable of protecting groups under conditions which will not be deprotected, wherein, P ^1, P ² and P ^3, methoxymethyl group, benzyloxymethyl group, methoxyethoxymethyl group, 2- (Trimethylsilyl) ethoxymethyl group, methylthiomethyl group, phenylthiomethyl group, 2,2-dichloro-1,1-difluoroethyl group, tetrahydropyranyl group, phenacyl group, p-bromophenacyl group, Ropropylmethyl group, allyl group, isopropyl group, cyclohexyl group, tert-butyl group, benzyl group, 2,6-dimethylbenzyl group, 4-methoxybenzyl group, o-nitrobenzyl group, 2,6-dichlorobenzyl group, 4- (dimethylaminocarbonyl) benzyl group, 9-anthrylmethyl group, 4-picolyl group, heptafluoro-p-tolyl group, tetrafluoro-4-pyridyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert- Butyldiphenylsilyl group, acetyl group, levulinoyl group, pivaloyl group, benzoyl group, 9-fluorenecarbonyl group, methoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, dimethylphospho Nyl group, dimethyl A compound selected from a ruthiophosphonyl group, a methanesulfonyl group, and a p-toluenesulfonyl group . Ring A, Ring B and Ring C may each independently have 1 to 3 substituents selected from an alkoxy group, an optionally halogenated alkyl group and a halogen atom, and P ¹ is an isopropyl group 24. The compound according to claim 23, wherein P ² is a benzyl group and P ³ is a methoxymethyl group. Formula (VII ')

(In the formula, A ring, B ring and C ring may each independently have a substituent, and R ⁴ is a hydrogen atom, a carboxyl group or —CO ₂ R ¹ (where R ¹ is halogenated) A lower alkyl group which may be substituted, an aryl group which may have a substituent or an aralkyl group which may have a substituent.), P ¹ represents a hydroxyl protecting group, and P ² represents shows the deprotected hydroxyl group capable of protecting groups under conditions that P ¹ is not deprotected, wherein, P ¹ and P ^2, methoxymethyl group, benzyloxymethyl group, methoxyethoxymethyl group, 2- (trimethylsilyl) ethoxymethyl Group, methylthiomethyl group, phenylthiomethyl group, 2,2-dichloro-1,1-difluoroethyl group, tetrahydropyranyl group, phenacyl group, p-bromophenacyl group, cyclopropyl Til, allyl, isopropyl, cyclohexyl, tert-butyl, benzyl, 2,6-dimethylbenzyl, 4-methoxybenzyl, o-nitrobenzyl, 2,6-dichlorobenzyl, 4- (Dimethylaminocarbonyl) benzyl group, 9-anthrylmethyl group, 4-picolyl group, heptafluoro-p-tolyl group, tetrafluoro-4-pyridyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenyl Silyl group, acetyl group, levulinoyl group, pivaloyl group, benzoyl group, 9-fluorenecarbonyl group, methoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, dimethylphosphonyl group , Dimethylthiophospho Nyl group, methanesulfonyl group, and p-toluenesulfonyl group . Ring A, Ring B and Ring C may each independently have 1 to 3 substituents selected from an alkoxy group, an optionally halogenated alkyl group and a halogen atom, and P ¹ is an isopropyl group in and, P ² is benzyl group, wherein compound of claim 25. Formula (I ')

(In the formula, A ring, B ring and C ring may independently have a substituent, - - - - represents a single bond or a double bond, P 1 ^'represents a hydroxyl-protecting group, P ^{2 ′} is a hydrogen atom, a hydroxyl protecting group that can be deprotected under conditions where P ^{1 ′} is not deprotected, or —SO ₃ P ⁴ (wherein P ⁴ is a sulfone that is not deprotected under conditions where P ^{1 ′} is deprotected) represents an acid protecting group.) indicates where the deprotected hydroxyl group capable of protecting group under the conditions P ¹ and P ^{1 'is} not deprotected, methoxymethyl group, benzyloxymethyl group, methoxyethoxymethyl group, 2 -(Trimethylsilyl) ethoxymethyl group, methylthiomethyl group, phenylthiomethyl group, 2,2-dichloro-1,1-difluoroethyl group, tetrahydropyranyl group, phenacyl group, p-bromophenacyl group, cyclopropylmethyl group Allyl group, isopropyl group, cyclohexyl group, tert-butyl group, benzyl group, 2,6-dimethylbenzyl group, 4-methoxybenzyl group, o-nitrobenzyl group, 2,6-dichlorobenzyl group, 4- (dimethylamino) Carbonyl) benzyl group, 9-anthrylmethyl group, 4-picolyl group, heptafluoro-p-tolyl group, tetrafluoro-4-pyridyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, Acetyl group, levulinoyl group, pivaloyl group, benzoyl group, 9-fluorenecarbonyl group, methoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, dimethylphosphonyl group, dimethylthio Phosphonyl group Methanesulfonyl group, and selected from p- toluenesulfonyl group, P ⁴ is 2,2,2-trichloroethyl group and selected from 2- (trimethylsilyl) ethyl group.) A compound represented by or a pharmaceutically In Acceptable salt. A ring, B ring and C ring may each independently have 1 to 3 substituents selected from an alkoxy group, an optionally halogenated alkyl group and a halogen atom, and P ^{1 ′} is isopropyl 28. The compound or a pharmaceutically acceptable salt thereof according to claim 27, wherein P ^{2 ′} is a hydrogen atom, a benzyl group or a 2,2,2-trichloroethoxysulfonyl group. General formula (XV)

(In the formula, A ring, B ring and C ring may independently have a substituent, ^{P 4} is shows a sulfonic acid protecting group, wherein, ^{P 4} is 2,2,2 Or a pharmaceutically acceptable salt thereof. The compound is selected from a trichloroethyl group and a 2- (trimethylsilyl) ethyl group . Ring A, Ring B and Ring C may each independently have 1 to 3 substituents selected from an alkoxy group, an optionally halogenated alkyl group and a halogen atom, and P ⁴ is 2, 30. The compound according to claim 29 or a pharmaceutically acceptable salt thereof which is a 2,2-trichloroethyl group.