WO2005026190A1 - Process for producing cyclic amine - Google Patents

Abstract

A process for easily producing a cyclic amine in high yield. The process for cyclic amine production comprises aminating, with hydrogen and ammonia, a cyclic ketone in which at least either of the carbon atoms in the α-positions with respect to the carbonyl group is tertiary or quaternary, wherein the amination is conducted in the presence of both a metallic catalyst comprising a platinum-group metal or a compound thereof and an ammonium salt. The metallic catalyst preferably is any of ruthenium, rhodium, palladium, ruthenium-carbon, rhodium-carbon, and palladium-carbon.

Description

_χ

Specification

 Method for producing aminated cyclic compounds

 Technical field

 [0001] The present invention relates to the removal of aminated cyclized ^ from $ ¾ ^.

To produce cyclocyclized ^);

 Background art

 [0002] Aminosteroid is known to have effects such as an antisensitivity effect and an anticancer effect.

 For example, 17-aminosteroids are anti-cancer drugs described in [

It is useful as a ^ m ^ i と し て? f «agent and the like.

 [0003] For example, in Non-Patent Document 1, the oxime form of estrone is reduced with sodium to obtain 17 j3-amino-1, 3, 5 (10) — Estratrien 3—;

 Non-patent document 1 Christina Lemini, Elia Cruz-Ramos et al., A comparative structural study of the steroid e imers: 17 j3 -amino-1, 3, 5 (10) _estratrien_3_ol, Π

-amino- 1, 3, 5 (10) _estratriene-3- o 丄, and some derivatives by ¹ H MR, and X-ray diffraction analysis Steroids, Elsevier Science Inc. (¾B), 1998, vol. 63, 55G- 56 non-赚Document 2 ShinoSawa, Hatae, Yada, Takagi, _"5 α by white ^^ Sumicho - cholestane one 3 on the selective reduction Aminoi &", Japan spoon ^^ 8 1 2 0 0 2 years lecture Proceedings Collection IP 5 7 6

 Disclosure of the invention

 'Inventive power S

 However, in this method, estrone was used as the raw material:

[0004] After that, in order to return, the power had to be advanced step by step, and it took a lot of trouble.

 The present invention is to solve such a conventional problem.

[0005] An object of the present invention is to provide a method for producing an aminoi-like compound such as a steroid by a simple and high yield. ·

 Means for deciding

Corrected paper (textile ¹ 1) [0006] The inventors of the present invention have made intensive efforts to solve the above-described problems, and as a result, have obtained a cyclic ketone by using a male of a white sickle or ^^^^^ square butterfly and an aluminum salt. Amino acid has been found to improve the yield of the resulting amino acid-modified ^! (Amino compound), leading to the present invention.

 [0007] That is, the production of the amino compound (aminated cyclic compound) of the present invention is carried out by cyclization ^!

(Amination of (carbonyl)) contained in (cyclic ketone) with hydrogen and ammonia to remove amination, which is a male or male compound containing f 白The addition of ammonium salt is a simple matter.

[0008] More specifically, the present invention provides a process for producing an aminated cyclic compound in which a cyclic ketone in which at least one carbon atom at the _α- position of the carbonyl group is a tertiary or quaternary is reacted with 7_k element and ammonia. In the past, the amylation was carried out in the presence of an amyloid in the presence of an ammodime salt with a white turtle or a salt thereof containing %% of the thiocyanate.

 [0009] According to the above, it is possible to aminate a cyclic ketone in which at least one carbon at the position of the carbonyl group is tertiary or quaternary by relatively simple removal with a high yield.

 [0010] Here, the term "white scythe" refers to ruthenium (Ru), rhodium (Rh), palladium (Pd), osmium (Os), iridium among the elements belonging to Groups 8 to 10 of the periodic table. (Ir) and platinum (Pt). Further, as examples of the conversion of a white man, there may be mentioned, for example, the elimination of the platinum group, halogen compounds such as bromine fiber and quince, «^, ί» ^, and rooster ^^.

 [0011] Displeased ^ S corner butterfly is a carrier of carbon, silica, alumina, silica-aluminum, especially a corner butterfly supported on carbon, if f is white. Good. As a result, the conversion of the starting material can be improved, and the yield of the finally obtained amino conjugate can be improved.

 [0012] The disgusting male horn butterfly is made of nondium, rhodium, rhodium, ruthenium-carbon (Ru-C), rhodium-carbon (Rh-C), or palladium-carbon (Pd-C). Either force is preferred, and more preferably rhodium, palladium, rhodium-carbon, or palladium-mukabon! It is preferable that it is a paradigm or paraffin foam. By using such a 蝶 corner butterfly,

Corrected paper (Hon ϋ9υ 2/1

The yield of solidified ^ l is more

.. Corrected form (Rule 91) It tends to be higher. Further, the use of ^ S square butterfly in carbon is preferable since the conversion ratio of the starting material tends to be improved. Also, from the viewpoint that the selectivity of the eight isomers is high, that is, from the viewpoint that the yield of the isomers is high, nonium, rhodium, palladium, palladium-palladium-carbon is preferable, and palladium and palladium-palladium are more preferable. One carbon force S is preferred, and platinum is particularly preferred.

 [0013] The production process of the present invention is suitably used for producing an aminosteroid by amination of a steroid ketone, and particularly, a steroid ketone in which the C-17 position is a carbonyl group (ketone group). It is preferably used, for example, in estrone's Amino-dani.

[0014]添口amount of廳己^蠘is, or of Silao being黝口^ / amount of 5 wt _^0/0 or more with respect Joke ton, preferably 5-2 0 weight ⁰ I More preferably, the amount is set to be 15 to 20% by weight.

[0015] For example, the annihilation angle 蠘 is a moth in which a sickle or its conversion ^ 5% is supported on a charcoal carrier ^ 1 0 0 wt _^0/0 or more with respect to, preferably 1 0 0-4 0 0 wt%, more preferably 3 0 0-4 0 that Do 0 wt%.

[0016]励卩amount of肅己Anmoniumu salt is preferably 3 0 wt _^0/0 or more with respect to tfjf應状ketone.

 [0017] is, for example, from 30 to 00 ° C, preferably from 50 to 70 ° C, particularly preferably from 60 to 70 ° C.

~ 70 ° C.

 [0018] In addition, it is preferable to perform the reaction under a pressure of 2 to 8 MPa, especially 4 to 6 MPa!

[0019] In another scythe of the present invention, a cyclic ketone such as a steroid ketone (a carbonyl group) is reduced with hydrogen and ammonia using an angle 蟣 to form an ammonium salt. The present invention provides tSt removal of aminated cyclization using an adhesive layer to suppress the hydroxylation of the ketone and to improve the yield of the amino compound.

 The invention's effect

 [0020] According to the present invention, an amino acid compound such as amino steroid can be produced easily and in good yield with good yield.

Corrected form (Rule 91 Four

BEST MODE FOR PRODUCING THE INVENTION

 [0021] In the production of the aminated cyclized compound (I) of the present invention, the carbonyl group of the cyclic ketone is converted to tf ^ S angle, including white そ の or its conversion, and ammonia. Under salt, 7_K element and ア ミ ノ amino by amination with ammonia! ^ To obtain a compound.

The cyclic ketone used in the present invention includes, for example, a cyclic ketone in which at least one hydrogen at the carbonyl group is woven, ie, a carbon (α-carbon) force of at least one of the carbonyl groups. He is a quaternary carbon cyclic ketone. More specifically, an alicyclic ketone (steroid ketone) having a steroid skeleton in which at least one hydrogen at the tertiary position of the carbyl group has been added is exemplified. Here, the steroid skeleton refers to a pentaphenanthrene skeleton having a peroxy mouth. Further, examples of ¾ which substitute for the hydrogen at the α-position include, but are not particularly limited to, an alkyl group (eg, methyl group) force S. The rings A to D in the steroid skeleton may have an edible bond. The manufacturing method of the present invention is particularly used for a steroid ketone or a tool having a carbonyl group (ketone group) at the C-17 position, such as estrone represented by the following formula (I).

[0023] [Formula 1]

 of

 [0024] As the ^ S angle butterfly used in the present invention, a dead angle butterfly containing ^ S of white sickle or ^ S of ^^ can be used. The term “white male” refers to the elements belonging to groups 8 to 10 of the periodic table: nonium (Ru), rhodium (Rh), palladium (Pd), osmium (Os), iridium (Ir), And platinum (Pt). Further, examples of the miscellaneous ^ M compounds include: «^, bromine ugly, halogenated ^ !,« ^, «^, and the like. In addition, the white base or its compound 1 may be converted to a carrier such as carbon, silicon, anoremina, or silica-alumina, preferably carbon. This is preferable since the transfer of the separated substance is improved. Also such gold

Corrected Invitation (Rule 91) _Five

Among the genus angle butterflies, Bruno Niumu, rhodium, Norajiumu, Roh Yuumu one carbon (R _U - C), rhodium one carbon (R h- C), and laid preferred palladium one carbon (P cL- C) is more , Rhodium, palladium, rhodium-carbon (R h—C), and ぴ. Radium bon (Pd_C), especially palladium and palladium-carbon, are preferred. When such a horn butterfly is used, the yield of amino acid compounds tends to be higher. Further, the conversion rate of the starting material tends to be improved at the age of being supported on carbon. Also, from the viewpoint that the cut ratio of the J3 body is high, that is, the yield of] 3 body is high, ruthenium, rhodium, palladium, and white palladium-carbon are preferable, and palladium is more preferable. White and palladium-carbon are preferable, and platinum is particularly preferable.

[0025] In the angle 担 持 supported by the carrier, the content of the or SS compound in the angle 0 is desirably 0:! To 10%. Specifically, 5% ruthenium-carbon (5% 111-, 5% rhodium-carbon (5% Rh-C), and 5% palladium-carbon (5% Pd-C) are preferable.

 [0026] The amount of mouth of Wei Kang butterfly is suggested that the amount of ^ S or ^ S

(E.g. steroid ketone) against, 5 weight _^0/0 or more, preferably 5-2 0 weight ⁰ I further preferably to 1 5-2 0 It force S Nozomu is an amount which is determined so that the weight% Masire, For example, for horned butterflies that consist only of the record or destruction of a scythe, the above amounts are used. In addition, when the ^ JS horn butterfly has an angle of 蠘 which carries 5% of the record of the male or the chemical on a carrier such as carbon, the amount of mouth of male angle 蠘 is a cyclic ketone (eg: against steroid ketone), 1 0 0 wt _^0/0 or more, preferably 1 0 0-4 0 0 wt ⁰ do more preferably is 3 0 0-4 0 0 wt%. If the pot size of the pot corner butterfly is less than the value shown below, there is a tendency for body S to be delayed. In addition, even if it exceeds the above-mentioned 5 horns, the effect of the square fiber does not change. Therefore, it is desirable to be within the above-mentioned fiber because of the cost.

 The ammonium salt used in the present invention includes, for example, ammonium fluoride, ammonium chloride, ammonium bromide, ammonium iodide, cock ammonium, and ammonium ammonium. Of these, halogenated ammonium is preferred, and ammonium chloride is particularly preferred.

 [0028] Further, the excitation ft of the ammonia is 30fi *% RJi with respect to the ketone serving.

Revised paper (Rule 91) 6

preferable. When the amount of ammonium salt advocated is in the upper margin, amino acids tend to be efficiently promoted.

 In the present invention, ammonia is used for the amino acid core, and the amount of ammonia is 1 mol or more, preferably 10 mol, per 1 mol of the raw material cyclic ketone (eg, steroid ketone). More preferably, it is preferably at least 50 mol.

 [0030] Further, during reductive amination, the temperature is preferably 30 to 100 ° C, more preferably 50 to 70 ° C,

 6 0-70 ° C, power s preferred level. But on! When it is in the box, the yield of the aminated cyclic compound (steroidamine) tends to be high without causing side effects.

[0031] The 7_R elemental pressure is preferably 2 to 8 MPa, particularly preferably 4 to 6 MPa. If the reaction pressure is in the range above ¾g, 畐 iHjS does not occur and

(Steroid amine) yield tends to increase.

 [0032] The fierce material used in the present invention is not particularly limited, but is preferably a nada which well dissolves ammonia, a cyclic ketone, and an ammonium salt. For example, a polar wister such as methanol, ethanol, or isopropyl alcohol may be used. Suitable for use! Although the amount of Nada is not particularly limited, it is usually 1 to 100 times, preferably 10 to 500 times the amount of the cyclic ketone.

 [0033] The addition amount of ammonium salt is not particularly limited, and a system containing a cyclic ketone may be advocated almost simultaneously with a horned butterfly. In addition, it is possible to excite the ammonium salt before adding the horn butterfly, and then add ^.

Next, the expected mechanism of the present invention will be described. Note that the present invention is not limited to the above description.

[0035] In the present invention, the addition of an ammonium salt suppresses the alcoholization of the secondary ketone and promotes the amination of the ketone ± S ^. It is thought that the yield of sulfide is improved.

[0036] To be more specific, it is generally considered that S ^ advances in the amide of ketone butterfly using 麵 corner butterfly, hydrogen and ammonia by the following Scheme.

Revised paper (Rule 91) [0037] [Dani 2]

O + NH ₃ NH

-H ₂ 0

 ,,, /

 ,,,

 , Si, St

 ketone (I) imine (Π)

Cat. Cat. + H,

 alcohol (IV) amine (ΙΠ)

 (target)

[0038] As shown in the above EScheme, in the reduction aminolysis reaction using hydrogen, diagonal and ammonia, competition between alcoholization and iminoization of ketone occurs. However, according to the present invention, by adding an ammonium salt, the formation of an intermediate, imine, becomes a forehead, and the formation of imine is improved. In addition, since the subsequent amining of the imine proceeds rapidly, the generation of the by-product alcohol (IV) is suppressed, thereby promoting the generation of the ^^ product amamine (III). Conceivable.

 [0039] Another H of the present invention is a cyclic ketone such as a steroid ketone, which is reductively oxidized with elemental and ammonia by using Tsutomu Kakuto; finally, an ammonium salt is formed. Thus, the aminated cyclization ^ せ る which suppresses the hydroxylation of the ketone which is an auxiliary β ^ and improves the yield of the aminated cyclization ^) » Note that the above description may be appropriately taken into account in addition to ** regarding the tut of Toshiya.

 [0040] [Wei example 1]

Ammonia about ^{1. 0 g (6. 0X10- 2 mo} 1) elaborate and溶力the, ethanol / Les 20 m 1, estrone (I) (n ^ (W ) Wi) 0. 054 g (2. OX 1 (T ⁴ mo 1), lutein Niumu angle蠘1 Omg (9. 9X10¾ιο 1), and Anmoniumu chloride _{(NH 4 C 1) 0. 20} g (3. 7X10- 3 mo 1) the fl¾ times car trial ^ "Tokurebu (Day; ^ pressure Ney, Start 200 Quick) ¾λ, hydrogen gas pressure 6. OMP a,

Corrected form (Rule 91) We went between 7/1.

 The obtained product was measured by gas chromatography (hereinafter, also referred to as GC).

Corrected form (Rule 91) 8

When the crude product was purified by silica gel column chromatography (hexane: form: methanol = 5: 4: 1), the target compound 17-amino-1,3,5 (10 ) One estratrien-3-ol (III) was obtained in 0.044 g (82% yield). At this time, the yield of estradiol (IV) produced as a by-product was 0.009 g (16% yield). The imine (II) produced as an intermediate in the reductive amination reaction was absent. Table 1 shows the results.

 The target compound (ΙΠ) was confirmed by 1H-NMR 270 MHz (CD-DMSO, standard

 6 6

 Quality TMS). Melting point was 228-230 ° C.

The scheme of the reaction is shown below.

[0045]

 Example 2

 Example 1 was carried out in the same manner as in Example 1 except that instead of luteuium, 0.20 g of a 5% ruthenium-carbon supported catalyst was used. The results are shown in Table 1.

[Example 3, Example 6]

 Example 1 was carried out in the same manner as in Example 1 except that the metal catalyst shown in Table 1 was used instead of ruthenium. The results are shown in Table 1.

[Examples 4-1-5]

In Example 2, the metal catalyst of Table 1 was used instead of the 5% ruthenium-carbon supported catalyst. Except having used, it carried out similarly to Example 2. Table 1 shows the results.

 [Comparative Examples 1 to 3]

 Example 1 was carried out in the same manner as in Example 1 except that the metal catalyst shown in Table 1 was used instead of ruthenium, and a salty ammonium was used. The results are shown in Table 1.

 [0050] [Table 1]

 1) The conversion indicates the rate at which the starting material was converted.

 2) Selectivity indicates the percentage of the substance produced by the conversion of the starting material.

 3) /? The ratio of the body to the body is the value obtained from the measurement results of 'HNM R and GC (trade name: CBP-1 (50 m), non-polar, manufactured by Shimadzu Corporation, Column). Those not listed are not measured.

 4) Others are expected to include substances with a saturated steroid ring A ring (benzene ring).

[Example 7-12]

 The reaction was carried out in the same manner as in Example 1, except that the conditions shown in Table 2 were used and the measurement was performed using GC (column: Agilent Technologies, Inc., trade name: DB-1701 (60 m), polarity). Table 2 shows the results.

[Comparative Examples 4-1 9]

The reaction was carried out in the same manner as in Example 1 except that the conditions shown in Table 2 were used and the measurement was performed using GC (Column: Agilent Technologies, Inc., trade name: DB-1701 (60 m), polarity). The result See Table 2.

[Table 2]

 Conversion indicates the rate at which the starting material was converted.

 The conversion data shown in the table are based on the data of GC (column Agilent Technologies, trade name: DB-170] (60 m), polarity).

As can be seen from the results in Tables 1 and 2, between the cases where Shiojiri Ammo was added and the case where Shiojiri Ammo was not added, the case where Shiojiri Ammo was added was the target substance. The selectivity of a certain steroid amine (III) tends to increase, and the selectivity of by-product estradiol (IV) tends to decrease. As a result, the by-product estradiol It was shown that ^^ of TJ (IV) was suppressed and that of steroidamine (III) was promoted. .

 In addition, the use of a horn butterfly supported on carbon: ^ improves the conversion of the starting material and improves the yield of steroidamine (III), compared with ^^ using the simple substance as square fiber. There is a tendency.

 [0055] The results in Tables 1 and 2 show that the results obtained by using lipodium, palladium and platinum! /, The conversion rate of the old age and the yield of steroidamine (in) were different from those of the other examples.低 Lower than ^ using butterflies, but it is considered that the conversion and yield can be improved by increasing the KiS time.

 [0056] In addition, the harm ij between the α-isomer of the target substance steroidamine (III) and the body is determined by a palladium-based fiber (Pd, Pd-C) and a white recording angle (Pt). Using: ^, especially 3 bodies ^ J¾¾ 7 this.

 Industrial applicability

[0057] According to the present invention, amination cyclization such as amino steroid can be easily performed;

Revised jfc paper (Rule ₉₁ )

Claims

12 Claims

[1] A cyclic ketone in which at least one carbon at the _α- position of the canoleponinole group is tertiary or quaternary can be converted to an amino acid with hydrogen and ammonia [^ t ^? 3 ^ i¾ made of Amino-Dai-Ry 匕 -Dani ^, which is to perform Amino-b® under Hakuo's ^ S or its keratinized fiber and ammonium salt.

 [2] The production of the amino-cyclized ^ # 1 according to claim 1, wherein the horned horn butterfly is a horny white male or a horn butterfly in which the compound thereof is carbon-exposed.

 [3] Disgusting Hornbutterfly is ruthenium, rhodium, noradium, ruthenium-carbon (Ru_C), rhodium-carbon (Rh_C), or palladium-carbon (Pd-C) 3. The process for producing the aminated cyclized compound according to claim 1 or claim 2.

 [4] The amino acid according to any one of claims 1 to 3, wherein the asymmetric ketone is a steroid ketone.

[5] A claim that claims that the C-17 position of the steroid ketone is a carbonyl group.

Amino cyclization according to 4 ^ / ^ m

 '

[6] The production of the aminated cyclic compound according to claim 4, wherein the asymmetric steroid ketone is an ester.

[7] The amount of addition of the horned butterflies shall be defined as 1% so that the amount of the white male or its compound that is recommended is determined to be 5% by weight or more based on the til ^ ketone. Claim

Removal of the aminated cyclization ^) described in 1-b.

Corrected form (Rule 91)