The way to obtain 6-oxa-8-isanalogous steroid estrogens


(57) Abstract:

Usage: as a lipid-lowering means and as an intermediate product in the synthesis of analogues of steroidal estrogens. The inventive product-6-oxa-8-sanalog steroid estrogens f-ly I, where R1= CH3C2H5C3H7; R2- H, CH3; R3= H, CH3; R4, R5= 0,

; n = 0;1. Reagent 1: 6-oxa-1,3,5(10),8,14-astreinte. Reagent 2: hydrogen over Raney Nickel. Reaction conditions: benzene at 80 - 110oC, a pressure of 10 to 15 MPa, the output 48,69%. Connection structure of f-crystals I:

The invention relates to the synthesis of biologically active analogues of steroid hormones, specifically to obtain 6-oxa-8-isanalogous steroid estrogens, having hypolipidemic activity and which intermediate compounds for the synthesis of other classes of substances.

Known only large-scale method of obtaining 6-oxa-8-isanalogous steroid estrogens catalytic hydrogenation of the corresponding 6-oxa-1,3,5(10),8,14-extrapontine in the presence of Pd/C (prototype).

The disadvantage of this method of production is the low yield of the target compounds due to the low the fir 6-oxa-8-isooctane obtained from the corresponding extrapontine with the release of 15% and methyl ether 18-methyl-6-oxa-8-isooctane with a yield of about 13% (in the latter case, an additional disadvantage is the multistage process).

The purpose of the invention to develop a method of obtaining 6-oxa-8-isanalogous of steroid oestrogens from the corresponding 6-oxa-1,3,5(10),8,14-extrapontine, which greatly improve the yield of the target compounds.

The objective is achieved by using as a catalyst of Raney Nickel, the hydrogenation reaction is carried out in benzene at 80-110aboutC and a pressure of 10-15 MPa.

P R I m e R 1. Synthesis of methyl ester of 6-oxa-8-isooctane (II).

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To a solution 3,49 g of 3-methoxy-6-oxa-1,3,5(10),8,14-astreinte-17-she (I) in 260 ml of benzene is added 5 g of freshly prepared Raney Nickel, hydrogenation of lead in a steel autoclave under stirring at 80-110aboutC and a pressure of 10-15 MPa. The reaction finished, when absorbed approximately 100-150-fold amount of hydrogen as compared with calculated. Then the reaction mixture is cooled to room temperature, the catalyst is filtered off, the solvent evaporated on a rotary evaporator. The residue is dissolved in 40 ml of pyridine, to the obtained solution was added with stirring the reagent Saretta prepared from 3.2 g of chromic anhydride and 35 ml of pyridine, the reaction mixture is left for a day at room temperature. The excess oxidizing agent is decomposed with 10 ml of alcohol, osadochnoi hydrochloric acid (1:1), three times with equal volumes of 5% aqueous solution of sodium acetate, then with water until neutral. The solvent is dried with sodium sulfate, the drying agent is filtered off, the ether removed on a rotary evaporator. The residue is crystallized from methanol. Gain of 2.45 g (69%) of target compound (II) with so pl. 144,5-147aboutC.

Mass spectrum, m/z (%): 286 (100) (M); 229 (4,0); 201 (70); 161 (82); 137 (10); 91 (9,9); 77 (10).

Calculated, 75,26; N 7,80.


Found, 75,35; N To $ 7.91.

P R I m m e R 2. Methyl ether 18-methyl-6-oxa-8-isooctane (IV).

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0.8 g of 18-methyl-3-methoxy-6-oxa-1,3,5(10),8,14-astreinte-17-she (III) hydronaut on the Raney Nickel followed by oxidation products of the reaction reagent Saretta as described in example 1. The target compound (IV) was isolated after crystallization from methanol, the yield of 0.39 g (48%), so pl. 138-139aboutC.

An NMR spectrum13With memorial plaques 130,0 (s-1); 107,3 (C-2); 158,8 (C-3); Of 101.3 (C-4); 155,0 (C-5); A 64.6 (C-7); To 36.7 (C-8 or C-9); 37,2 (C-8 or C-9); 118,9 (C-10); 27,5 (C-11 and C-12); 50,1 (C-13); And 47.0 (C-14); 20,6 (C-15 or C-18); 20,2 (C-15 or C-18); 35,3 (C-16); 217,5 (C-17); And 8.4 (C-18a).

Calculated With 75,97; N 8,05.

Found, C 75,82; N 8,14.

P R I m e R 3. Methyl ester of 6-oxa-D-Homo-8-isooctane (VI).


Range of PMR, , M. D. of 1.08 (3H, WITH18-N3); 3,76 (3H, CH3O); 4,08-4.30 m (2N, WITH7H2); 6,38 d (1H, WITH4N); 6,50 DD (1H, WITH2N); 7,02 d (1-N).

Calculated With 75,97; N 8,05.

Found, 75,85; N 8,21.

P R I m e R 4. Acetate 3-methyl ester 7-methyl-6-oxa-8-soustredila (VIII).

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3,82 g of 17-acetoxy-7-methyl-3-methoxy-6-oxa-1,3,5(10),8,14-extrapontine in 270 ml of benzene hydronaut in the presence of 5 g of Raney Nickel under the conditions described in example 1. After the reaction the catalyst is filtered off, the solvent is removed on a rotary evaporator and the residue is crystallized from methanol. Obtain 1.78 g (46%) of the desired product with so pl. 101-104aboutAnd 113-114,5aboutC.

Range of PMR, , memorial plaques to 0.92 (3H, WITH18H3); 1,45 D. (3H, J 6 Hz, WITH7-CH3); 2,02 (3H, CH3CO); 3,74 (3H, CH3O); 4.2-4.5 m (1H, WITH7N); 4,62 m (1H, WITH17N); 6,3-6,5 m (2N, WITH2N and4N); 6,95 d (1H, J 8 Hz, WITH1N).

Calculated With 73,23; N 8,19.

Found, 73,44; N 8,35.

P R I m e R 5. AC-1,3,5(10),8,14-extrapontine (IX) hydronaut, as described in example 4. The reaction product produce by crystallization from methanol. Yield 1.55 g (44%), so pl. 106-110aboutC.

Range of PMR, , M. D. 0,86 t (3H, J 7 Hz, CH3-CH2); 2,00 (3H, CH3WITH); to 3.73 (3H, CH3O); 4,19 m (2N, WITH7H2); 4,71 m (1H, WITH17N); 6,35-6,57 m (2N, WITH2N and4H); 7.03 is d (1H, WITH1-N).

Calculated With 73,71; N 8,44.

Found, 73,88; N 8,45.

P R I m e R 6. Methyl ester of 16,16-dimethyl-6-oxa-D-Homo-8-isooctane (XII). 1 g 16,16-dimethyl-3-methoxy-6-oxa-D-Homo-1,3, 5(10),8,14-astreinte-17A-she (XI) hydronaut on the Raney Nickel followed by oxidation products of the reaction reagent Saretta as described in example 1. The target connection allocate crystallization from methanol, the yield of 0.87 g (39%), so pl. 150,5-152,5aboutC.

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An NMR spectrum13With memorial plaques 130,0 (s-1); To 107.6 (C-2); 159,1 (C-3); Of 101.5 (C-4); 155, 1mm (C-5); 64,1 (C-7); 39,1 (C-8 and C-9)*; 119,5 (C-10); 27,8 (C-11); 31,9 (C-12); With 46.6 (C-13); 41,0 (C-14 and C-15)*; 35,0 (C-16); 50,8 (C-17); 214,0 (C-17A); 26,3 and 32.5 (methyl group at C-16); 55,3 (CH3) (* The assignment is not unique).

Calculated With 76,79; N 8,59.

Found, 76,69; N 8,80.

Thus, the proposed method of obtaining 6-oxa-8-isanalogous steroid is antigenome method get with outputs respectively 69% and 48% whereas by a known method outputs are 13% and 15%

The proposed method allows to synthesize compounds containing substituents near double bonds in the original 6-oxa-1,3,5(10),8,14-extrapontine (examples 4 and 6). At the same time when the synthesis of an analog of (VIII) (example 4) is known a method of the target product to allocate failed (O. Dann et al. Chem. Ber. 1971, Bd. 104, No. 10. S. 3313). The proposed method can obtain analogues of estrogen with a six-membered ring (examples 3 and 6), as well as connections with voluminous Deputy at C-13 (example 5).


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where R1- CH3C2H5C3H7;

R2- H, CH3;

R3- H, CH3;

R4, R5- O;

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n = 0,1,

includes catalytic hydrogenation of 6-oxa-1,3,5(10),8,14-extrapontine, characterized in that, with a view to increasing output 8-isanalogous hydrogenation is carried out in benzene in the presence of Raney Nickel in the temperature range 80 - 110oC at a pressure of 10 to 15 MPa.


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