RU2057140C1 - Method of synthesis of 6-oxa-8-isoanalogs of steroid estrogens - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: 6-oxa-8-isoanalog of steroid estrogens of the formula (I) where R₁=CH₃, C₂H₅, C₃H₇; R₂ - H, CH₃; R₃ - H, CH₃; R₄, R₅ =O,

; n = 0. Reagent 1: 6-oxa-1,3,5(10),8,14-estrapentene. Reagent 2: hydrogen over Raney nickel. Reaction conditions: in benzene at 80-110 C, under pressure 10-15 MPa, the yield is 48.69%. Structure of compound of the formula I:

EFFECT: improved method of synthesis.

Description

 The invention relates to the synthesis of biologically active analogues of steroid hormones, particularly to the production of 6-oxa-8-iso analogs of steroid estrogens having lipid-lowering activity and which are intermediate compounds for the synthesis of other classes of substances.

 The only known method for large-scale production of 6-oxa-8-iso analogs of steroid estrogens is the catalytic hydrogenation of the corresponding 6-oxa-1,3,5 (10), 8,14-estrapentaenes in the presence of Pd / C (prototype).

 The disadvantage of this production method is the low yield of the target compounds, due to the low stereoselectivity of the reaction, which forces the use of multi-stage synthesis schemes.

 6-oxa-8-isoestrone methyl ester is obtained from the corresponding estrapentaene with a yield of 15% and 18-methyl-6-oxa-8-isoestrone methyl ester with a yield of about 13% (in the latter case, an additional disadvantage is the multi-stage process).

 The purpose of the invention is the development of a method for producing 6-oxa-8-iso analogs of steroid estrogens from the corresponding 6-oxa-1,3,5 (10), 8,14-estrapentaenes, which allows to significantly increase the yield of target compounds.

The objective is achieved using a Raney nickel catalyst, the hydrogenation reaction is carried out in benzene at 80-110 ^{° C} and a pressure of 10-15 MPa.

 PRI me R 1. Synthesis of methyl ester of 6-oxa-8-isoestrone (II).

К раствору 3,49 г 3-метокси-6-окса-1,3,5(10),8,14-эстрапентаен-17-она (I) в 260 мл бензола добавляют 5 г свежеприготовленного никеля Ренея, гидрирование ведут в стальном автоклаве при перемешивании при 80-110^оС и давлении 10-15 МПа. Реакцию заканчивают, когда поглотится примерно 100-150-кратное количество водорода по сравнению с рассчитанным. Затем реакционную смесь охлаждают до комнатной температуры, катализатор отфильтровывают, растворитель упаривают на ротационном испарителе. Остаток растворяют в 40 мл пиридина, к полученному раствору при перемешивании добавляют реактив Саретта, приготовленный из 3,2 г хромового ангидрида и 35 мл пиридина, реакционную смесь оставляют на сутки при комнатной температуре. Избыток окислителя разлагают 10 мл спирта, осадок отфильтровывают и промывают 350 мл эфира. Объединенную органическую фазу трижды промывают равным объемом разбавленной соляной кислоты (1:1), трижды равным объемом 5%-ного раствора уксуснокислого натрия, затем водой до нейтральной реакции. Растворитель сушат сульфатом натрия, осушитель отфильтровывают, эфир удаляют на ротационном испарителе. Остаток кристаллизуют из метанола. Получают 2,45 г (69%) целевого соединения (II) с т. пл. 144,5-147^оС.

To a solution of 3.49 g of 3-methoxy-6-oxa-1,3,5 (10), 8,14-estrapentaen-17-one (I) in 260 ml of benzene add 5 g of freshly prepared Raney nickel, hydrogenation is carried out in steel autoclave with stirring at 80-110 ^about C and a pressure of 10-15 MPa. The reaction is completed when approximately 100-150 times the amount of hydrogen is absorbed compared to the calculated one. Then the reaction mixture was cooled to room temperature, the catalyst was filtered off, and the solvent was evaporated on a rotary evaporator. The residue was dissolved in 40 ml of pyridine, the Saretta reagent prepared from 3.2 g of chromic anhydride and 35 ml of pyridine was added to the resulting solution with stirring, and the reaction mixture was left at room temperature for one day. Excess oxidizing agent is decomposed with 10 ml of alcohol, the precipitate is filtered off and washed with 350 ml of ether. The combined organic phase is washed three times with an equal volume of dilute hydrochloric acid (1: 1), three times with an equal volume of a 5% sodium acetate solution, then with water until neutral. The solvent is dried with sodium sulfate, the desiccant is filtered off, the ether is removed on a rotary evaporator. The residue is crystallized from methanol. Get 2.45 g (69%) of the target compound (II) with so pl. 144.5-147 ^about S.

 Mass spectrum, m / z (%): 286 (100) (M); 229 (4.0); 201 (70); 161 (82); 137 (10); 91 (9.9); 77 (10).

 Calculated, C 75.26; H, 7.80.

C ₁₈ H ₂₂ O ₃ .

 Found, C 75.35; H, 7.91.

 PRI me R 2. Methyl ester of 18-methyl-6-oxa-8-isoestrone (IV).

0,8 г 18-метил-3-метокси-6-окса-1,3,5(10),8,14-эстрапентаен-17-она (III) гидрируют на никеле Ренея с последующим окислением продуктов реакции реактивом Саретта, как описано в примере 1. Целевое соединение (IV) выделяют после кристаллизации из метанола, выход 0,39 г (48%), т. пл. 138-139^оС.

0.8 g of 18-methyl-3-methoxy-6-oxa-1,3,5 (10), 8,14-estrapentaen-17-one (III) is hydrogenated with Raney nickel, followed by oxidation of the reaction products with Saretta reagent, as described in example 1. The target compound (IV) is isolated after crystallization from methanol, yield 0.39 g (48%), so pl. 138-139 ^about S.

¹³ C NMR spectrum, δ, ppm 130.0 (C-1); 107.3 (C-2); 158.8 (C-3); 101.3 (C-4); 155.0 (C-5); 64.6 (C-7); 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); 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); 8.4 (C-18a).

 Calculated, C 75.97; H, 8.05.

S ₁₉ H ₂₄ O ₃
Found C 75.82; H, 8.14.

 PRI me R 3. Methyl ether 6-oxa-D-homo-8-isoestron (VI).

5,37 г 3-метокси-6-окса-D-гомо-1,3,5(10),8,14-эстрапентаен-17а-она (V) гидрируют на никеле Ренея с последующим окислением продуктов реакции, как описано в примере 1. Целевое соединение (VI) кристаллизуют из метанола, получают 3,77 г препарата (69%) с т. пл. 138-139,5^оС.

5.37 g of 3-methoxy-6-oxa-D-homo-1,3,5 (10), 8,14-estrapentaen-17a-one (V) is hydrogenated with Raney nickel, followed by oxidation of the reaction products as described in Example 1. The target compound (VI) is crystallized from methanol to obtain 3.77 g of the drug (69%) with a mp. 138-139.5 ^about S.

PMR spectrum, δ, ppm 1.08 s (3H, C ¹⁸ -H ₃ ); 3.76 s (3H, CH ₃ O); 4.08-4.30 m (2H, C ⁷ H ₂ ); 6.38 d (1H, C ⁴ -H); 6.50 dd (1H, C ² -H); 7.02 d (C ¹ -H).

 Calculated, C 75.97; H, 8.05.

S ₁₉ H ₂₄ O ₃
Found, C 75.85; H, 8.21.

 PRI me R 4. Acetate of 3-methyl ester 7 α-methyl-6-oxa-8-isoestradiol (VIII).

3,82 г 17 β-ацетокси-7 -метил-3-метокси-6-окса-1,3,5(10),8,14-эстрапентаена в 270 мл бензола гидрируют в присутствии 5 г никеля Ренея в условиях, описанных в примере 1. После окончания реакции катализатор отфильтровывают, растворитель удаляют на ротационном испарителе, остаток кристаллизуют из метанола. Получают 1,78 г (46%) целевого продукта с т. пл. 101-104^оС и 113-114,5^оС.

3.82 g of 17 β-acetoxy-7-methyl-3-methoxy-6-oxa-1,3,5 (10), 8,14-estrapentaene in 270 ml of benzene is hydrogenated 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, the residue is crystallized from methanol. Obtain 1.78 g (46%) of the target product with so pl. 101-104 ^о С and 113-114.5 ^о С.

PMR spectrum, δ, ppm 0.92 s (3H, C ¹⁸ H ₃ ); 1.45 d (3H, J 6 Hz, C ⁷ -CH ₃ ); 2.02 s (3H, CH ₃ CO); 3.74 s (3H, CH ₃ O); 4.2-4.5 m (1H, C ⁷ N); 4.62 m (1H, C ¹⁷ N); 6.3-6.5 m (2H, C ² H and C ⁴ N); 6.95 d (1H, J 8 Hz, C ¹ N).

 Calculated, C 73.23; H, 8.19.

C ₂₁ H ₂₈ O ₄
Found, C, 73.44; H, 8.35.

 PRI me R 5. Acetate of 3-methyl ester of 18-ethyl-6-oxa-8-isoestradiol (X).

3,5 г 17 β-ацетокси-3-метокси-18-этил-6-окса-1,3,5(10),8,14-эстрапентаена (IX) гидрируют, как описано в примере 4. Продукт реакции выделяют кристаллизацией из метанола. Выход 1,55 г (44%), т. пл. 106-110^оС.

3.5 g of 17 β-acetoxy-3-methoxy-18-ethyl-6-oxa-1,3,5 (10), 8,14-estrapentaene (IX) is hydrogenated as described in example 4. The reaction product is isolated by crystallization from methanol. Yield 1.55 g (44%), mp. 106-110 ^about C.

PMR spectrum, δ, ppm 0.86 t (3H, J 7 Hz, CH ₃ -CH ₂ ); 2.00 s (3H, CH ₃ CO); 3.73 s (3H, CH ₃ O); 4.19 m (2H, C ⁷ H ₂ ); 4.71 m (1H, C ¹⁷ N); 6.35-6.57 m (2H, C ² H and C ⁴ N); 7.03 d (1H, C ¹ -H).

 Calculated, C 73.71; H, 8.44.

C ₂₂ H ₃₀ O ₄
Found, C, 73.88; H, 8.45.

PRI me R 6. Methyl ester of 16,16-dimethyl-6-oxa-D-homo-8-isoestrone (XII). 1 g of 16,16-dimethyl-3-methoxy-6-oxa-D-homo-1,3, 5 (10), 8,14-estrapentaen-17a-one (XI) is hydrogenated with Raney nickel, followed by oxidation of the reaction products Saretta's reagent, as described in example 1. The target compound is isolated by crystallization from methanol, yield 0.87 g (39%), so pl. 150.5-152.5 ^about C.

Спектр ЯМР ¹³С, δ, м.д. 130,0 (С-1); 107,6 (С-2); 159,1 (С-3); 101,5 (С-4); 155,1 (С-5); 64,1 (С-7); 39,1 (С-8 и С-9)*; 119,5 (С-10); 27,8 (С-11); 31,9 (С-12); 46,6 (С-13); 41,0 (С-14 и С-15)*; 35,0 (С-16); 50,8 (С-17); 214,0 (С-17а); 26,3 и 32,5 (метильные группы при С-16); 55,3 (СН₃О) (* отнесение не однозначно).

¹³ C NMR spectrum, δ, ppm 130.0 (C-1); 107.6 (C-2); 159.1 (C-3); 101.5 (C-4); 155.1 (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); 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 groups at C-16); 55.3 (CH ₃ O) (* assignment is not unambiguous).

 Calculated, C 76.79; H, 8.59.

C ₂₁ H ₂₈ O ₃
Found, C, 76.69; H, 8.80.

Thus, the proposed method for producing 6-oxa-8-iso analogs of steroid estrogens has a significant advantage over the known one. As can be seen from examples 1 and 2, steroids (II) and (IV) according to the proposed method are obtained with yields of 69% and 48%, respectively, while according to the known method, the yields are 13% and 15%
The proposed method allows to synthesize compounds containing substituents near double bonds in the starting 6-oxa-1,3,5 (10), 8,14-estrapentaenes (examples 4 and 6). At the same time, in the synthesis of analogue (VIII) (example 4) by the known method, the target product could not be isolated (O. Dann et al. Chem. Ber. 1971, Bd. 104, N 10. S. 3313). By the proposed method, it is possible to obtain analogues of estrogen with a six-membered ring (examples 3 and 6), as well as compounds with a bulky substituent at C-13 (example 5).

Claims (1)

METHOD FOR PRODUCING 6-OXA-8-ISOANALOGUES OF STEROID ESTROGENS of the general formula

where R ₁ is CH ₃ , C ₂ H ₅ , C ₃ H ₇ ;
R ₂ is H, CH ₃ ;
R ₃ is H, CH ₃ ;
R ₄ , R ₅ is O;

n = 0.1
including catalytic hydrogenation of 6-oxa-1,3,5 (10), 8,14-estrapentaenes, characterized in that, in order to increase the yield of 8-iso analogs, hydrogenation is carried out in benzene in the presence of Raney nickel in the temperature range of 80 - 110 ^o C at a pressure of 10 to 15 MPa.