JP3204368B2 - Preparation of optically active amides - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD [0001] The present invention is represented by the following formula (4), which has excellent HIV protease inhibitory activity and is useful as an intermediate of saquinavir (EP432694) which is expected as an anti-AIDS drug. The present invention relates to a method for producing decahydro (4aS, 8aS) isoquinoline-3 (S) -carboxamides.

[0002]

2. Description of the Related Art As a method for producing decahydro (4aS, 8aS) isoquinoline-3 (S) -carboxamides,
N-ter in which tert-butylamide is introduced into amide
A method for producing t-butyl-decahydro (4aS, 8aS) isoquinoline-3 (S) -carboxamide is known (US Pat. No. 5,256,783). In the process described in this patent, L-phenylalanine is first N-protected with benzyl chloroformate and then led to N-tert-butylamide via a mixed acid anhydride (84.3%). Reaction with formaldehyde in the presence of an acid catalyst to form tetrahydroisoquinoline (66%)
N-deprotection by catalytic reduction using (79%)
Finally, a decahydroisoquinoline compound is obtained with a Rh catalyst (5.
9%). However, this method has disadvantages such as requiring multiple steps, having a low yield step, requiring strict control of the reaction in order to maintain optical purity, and using expensive Rh. It is not practical for actual industrial production, and the development of a simpler production method has been desired.

Usually, a heterogeneous metal catalyst such as Rh or Pt is used for the reduction of the aromatic ring nucleus having a functional group. On the other hand, Ru is also known to reduce the nucleus of the aromatic ring, but is not known about stereoselective reduction.

On the other hand, as a method for producing tetrahydroisoquinoline-3-carboxamide, which is the above intermediate, tetrahydroisoquinoline-3-carboxylic acid is protected with a benzyloxycarbonyl group (66.5%), and then NCA is added using phosphorus pentachloride. (69%), a method of converting it to an amide by reacting it with an amine (57%) has been reported (Ch
imika Chronika, New Series, 18 , 3, 3, 1989) is carried out in a racemic form, so it is not known whether the optical activity is retained, the yield of each step is low, and undesired by-products and It is not industrially suitable because it produces a lot of industrial waste.

[0005]

SUMMARY OF THE INVENTION Decahydro (4aS,
8aS) Isoquinoline-3 (S) -carboxamides are to be selectively and industrially useful.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have converted tetrahydroisoquinoline-3 (S) -carboxylic acid, which has been industrially established, to phosgene and phosgene. By reacting with either a dimer or triphosgene, tetrahydroisoquinoline carboxylic acid N-carboxy anhydride (NCA)
To produce tetrahydroisoquinolinecarboxamide in two steps in high yield by producing Namide with high yield and without impairing optical activity, and further reacting with various amines to open NCA to obtain an amide form. And completed the present invention.

That is, the present invention provides a compound represented by the following formula (2) by reacting a tetrahydroisoquinoline-3 (S) -carboxylic acid represented by the following formula (1) with at least one of phosgene, phosgene dimer and triphosgene. And then reacting with amines to produce a tetrahydroisoquinoline-3 (S) -carboxamide derivative represented by the following formula (3), and further reducing in the presence of a metal catalyst. A method for producing a decahydro (4aS, 8aS) isoquinoline-3 (S) -carboxamide derivative represented by the following formula (4), which comprises performing a reaction:

[0008]

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(Wherein, R ₁ represents hydrogen or lower alkyl having 1 to 6 carbon atoms)

[0010] Further, the nuclear reduction of the aromatic ring of tetrahydroisoquinolinecarboxamide was studied. In addition to the commonly used expensive metal catalysts such as Rh and Pt, Ru was used for stereoselection while maintaining optical activity. It was found that the aromatic ring was nuclear-reduced and the yield was significantly higher than that of Rh, and the present invention was completed.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The tetrahydroisoquinoline carboxylic acid used in the present invention is obtained by reacting phenylalanine with formaldehyde in the presence of an acid catalyst (Pictet Spengle).
r reaction), it has been known for a long time (Chem. Pharm. Bull., 31 , 312, 1983;
7466), which are produced in large quantities on an industrial scale as intermediates of the ACE inhibitor quinapril. Tetrahydroisoquinoline-3 (S) -carboxylic acid (1) is reacted with at least one of phosgene, phosgene dimer, and triphosgene (hereinafter abbreviated as phosgene, etc.) to produce N-carboxy anhydride (2) (hereinafter abbreviated as NCA). In the reaction, NCA can be obtained by dissolving or suspending tetrahydroisoquinoline-3 (S) -carboxylic acid in an organic solvent and adding phosgene or the like thereto. Conversely, phosgene or the like can be dissolved in an organic solvent, and tetrahydroisoquinoline-3 (S) -carboxylic acid can be added thereto. Phosgene or the like used in the reaction may be a monomer (phosgene gas), a dimer (phosgene dimer), or a trimer (triphosgene), and preferably 1 to 10 equivalents of the starting material (1), preferably Is used in an amount of 1.1 to 1.3 equivalents. The organic solvent to be used is not particularly limited as long as it does not react with phosgene. Specific examples include tetrahydrofuran, dichloromethane, 1,2-dichloroethane, toluene, methyl tert-butyl ether and ether. In the next reaction, tetrahydrofuran (THF) is preferred from the viewpoint that it does not react with the amine and dissolves the product, tetrahydroisoquinoline-3 (S) -carboxamide. The reaction is carried out at a temperature of 0 to 100 ° C, preferably 50 to 60 ° C, and the reaction is completed in 0.1 to 36 hours, usually 2 to 5 hours.

The NCA (2) obtained by the reaction is isolated as crystals by removing excess phosgene and the like by a usual method, and then cooling the reaction solution or adding an inert solvent. it can. Hexane as an inert solvent,
Heptane, toluene and the like can be mentioned. Note that NCA (2) (tetrahydroisoquinoline-3) represented by the following formula:
(S) -carboxylic acid N-carboxy anhydride) is a novel compound, and by passing through this compound, the next tetrahydroisoquinoline-3 can be maintained while maintaining optical activity.
(S) -carboxamide derivative (3) can be easily derived.

[0013]

Embedded image

Usually, NCA (2) can be directly used in the next amidation step. That is, the amidation is achieved by reacting the NCA obtained above with ammonia or any of lower primary amines having 1 to 6 carbon atoms. Preferably, a method of adding a solution of NCA to amines is used. Be taken. The solvent for dissolving NCA is not particularly limited as long as it does not react with NCA or amines, but tetrahydrofuran (THF), dichloromethane and the like are preferable because they are solvents used in the pre-reaction. Other than these, 1,2-dichloroethane, toluene, methyl tert-butyl ether,
Ether or the like may be used. The amines used in the reaction are specifically ammonia, primary alkylamines having 1 to 6 carbon atoms, preferably primary alkylamines having 1 to 4 carbon atoms, such as methylamine, ethylamine, propylamine, Isopropylamine, butylamine, isobutylamine, sec-butylamine, tert-butylamine, pentylamine, hexylamine and the like.
In order to lead to the target compound saquinavir of the present invention,
Tert-butylamine is preferable because it can be used as it is. The amine may be dissolved in a solvent or used directly as a solvent. The amine is 1 to 50 equivalents to NCA,
Preferably, 2 to 5 equivalents are used. The reaction temperature is -50
The reaction proceeds almost quantitatively at a temperature of about 70 ° C., preferably 0 to 20 ° C., and the reaction time is 0.01 to 24 hours, usually 1 to 5 hours.
Time.

Of the tetrahydroisoquinoline-3 (S) -carboxamide derivatives (3) obtained by the above reaction, R
Compounds in which ₁ is a tert-butyl group are separately described in US Pat.
All the analytical values agreed with the standard synthesized by the production method described in US Pat.

The yield from phenylalanine to N-tert-butyltetrahydroisoquinolinecarboxamide is 63% when calculated with reference to the yield (81%) of conversion of phenylalanine to tetrahydroisoquinoline carboxylic acid described in JP-A-6-157466. And US5
Considering that at 256,783 it is 44%, a yield improvement of more than 40% has been achieved.

The following tetrahydroisoquinoline-3
The step of reducing the (S) -carboxamide derivative (3) to decahydroisoquinoline-3 (S) -carboxamide derivative (4) is performed by using tetrahydroisoquinoline-3
It can be achieved by dissolving (S) -carboxamide in a solvent, adding a metal catalyst and reacting in the presence of hydrogen. Conventionally used metal catalysts for the reaction include Rh, P
In addition to t, there is Ru. In particular, when Ru is used, the reduction proceeds stereoselectively without racemization, and the decahydro (4aS, 8aS) isoquinoline-3 (S) -carboxamide derivative (4) can be obtained in good yield. Ru / C and Ru / alumina can be used as Ru. As the solvent used in the reaction, there is no problem as long as it does not have an aromatic ring and does not react with the substrate, alcohols,
Examples thereof include esters, acetic acid, and water, and specific examples include methanol, ethanol, 2-propanol, butanol, ethyl acetate, and isopropyl acetate. 2-
Propanol is preferred in view of the vapor pressure during the reaction and the treatment after the reaction. Hydrogen pressure is 5 to 200 atm, preferably 10 to 5
0 atm is preferable in terms of economy and reactivity. Reaction temperature is 2
0 to 200 ° C., preferably 80 to 120 ° C. is preferable from the viewpoint of maintaining optical purity. After the reaction, the catalyst is separated by filtration, concentrated, and easily purified by crystallization from an appropriate solvent, for example, hexane or heptane which is a hydrocarbon solvent. Alternatively, it can be crystallized as a salt such as hydrochloric acid or an organic acid. The obtained crystals do not contain stereoisomers and are easy to isolate and purify, which makes it possible to provide an industrially useful method.

[0018]

【Example】

(Synthesis Example 1) Tetrahydroisoquinoline-3 (S)-
Carboxylic acid (1.00 g; 5.64 mm, manufactured by Aldrich)
ol) with triphosgene (0.67 g; 2.26 mmol)
1) A solution of (1) in tetrahydrofuran (10 mL) was heated and stirred at 60 ° C for 3 hours. After the reaction, the solvent was distilled off, the residue was dissolved in tetrahydrofuran (5 mL) and dichloromethane (10 mL), and the slurry was added dropwise at 7 ° C or lower to a solution of tert-butylamine (2.97 mL; 28.2 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at room temperature overnight. Acidify with 1N hydrochloric acid (30 mL),
The layers were separated, and the organic layer was back-extracted with 1N hydrochloric acid (10 mL) three times toward the aqueous layer. All aqueous layers were combined, made alkaline with 4N sodium hydroxide solution (20 mL) and extracted twice with dichloromethane (20 mL). After the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off, 1.11 g of a pale yellow solid was obtained (84.7% yield). When 1.00 g of the pale yellow solid obtained above was recrystallized by heating from hexane (8 mL), 0.918 g of N-tertbutyltetrahydroisoquinolinecarboxamide was obtained as white crystals (crystallization yield: 91.8). %).

Optical rotation: [α] ^D ₂₀ = −111.57 (c
= 1.0, MeOH) ¹ H NMR (CDCl ₃ ): 7.2-7.1, 7.1-7.0 (m, 5H, arom,
NHCO), 3.99 (s, 2H, NH-C H ₂ -arom), 3.43 (dd, 1H, J = 10.7Hz,
5.1Hz , NH-C H -CO), 3.21 (dd, 1H, J = 16.5Hz, 4.9Hz, C H-C H ₂ -a
rom), 2.79 (dd, 1H , J = 16.5Hz, 10.7Hz, CH-C H 2 -arom), 1.65
(s, 1H, N H -CH2 -arom), 1.37 (s, 9H, t-Bu) 13 CNMR (CDCl 3): 172.2,135.8,
134.5, 129.3, 126.5, 126.1, 1
25.5, 57.1, 50.6, 47.8, 31.1,
28.7

(Synthesis Example 2) A tetrahydrofuroisoquinoline carboxylic acid (2.00 g; 11.3 mmol) and triphosgene (1.33 g; 4.48 mmol) in tetrahydrofuran (20 mL) were heated and stirred at 60 ° C. for 3 hours. The solution was filtered while hot, and the filtrate was cooled at 0 ° C. for 4 hours to obtain 781 mg of pale yellow NCA crystals (yield 34.1%).

IR: 1635, 1459, 1403, 1
318, 744 (cm ^-1 ) ¹ H NMR (DMSO-d ₆ ): 7.3-7.2 (m, 4H, arom), 4.7
8 (d, 1H, J = 16.7Hz, arom-C H 2 -NH), 4.46 (d, 1H, J = 16.7Hz, ar
om-C H ₂ -NH), 4.62 (dd, 1H, J = 5.6Hz, 10.8Hz, CH-N), 3.3-3.1
(m, 2H, CO-CH -C H 2) 13 CNMR (DMSO-d 6): 169.8,150.7 (N-CO-O), 1
31.2, 130.4, 129.4, 127.0, 126.9, 126.7, 54.3, 41.9, 28.9

Synthesis Example 3 N-tert-butyltetrahydroisoquinolinecarboxamide (2.00 g;
8.61 mmol) and 5% Ru / C (0.20 g; 9
8.4 umol) of 2-propanol (20 mL) was stirred in an autoclave at room temperature at a hydrogen pressure of 30 atm, stirred at 100 ° C for 20 hours, cooled, and filtered by a catalyst. The filtrate was evaporated under reduced pressure, and crystallized from hexane to obtain primary crystals (yield 1.07 g; 52.1%) and secondary crystals (yield 0.42 g; 20.7%). .

Melting point: 116-117 ° C. Optical rotation: [α] ^D ₂₀ = -72.7 (c = 0.5, methanol) ¹ HNMR (CDCl ₃ ): 6.54 (bs, 1H, CO-NH), 3.1 -3.0
(m, 1H, C H -NH ), 2.9-2.7 (m, 2H, C H 2 -NH), 1.9-1.2 (m, 13H, cy
clohexane-ring, CO-CH-C H 2, CH-N H ), 1.37 (s, 9H, t-Bu) ¹³ C NMR (CDCl ₃ ): 173.5 (CO), 61.7, 51.7, 50.4,
35.5, 34.4, 31.7, 29.6, 28.8, 26.4, 24.9, 20.7

(Synthesis Example 4) Phosgene gas (1.17 kg) was blown into a mixed solution of dichloromethane (9.8 L) and tetrahydrofuran (1.7 L) cooled to -5 ° C. In contrast, tetrahydroisoquinoline-
A solution of 3 (S) -carboxylic acid (1.05 Kg) in dichloromethane (4.5 L) and tetrahydrofuran (0.8 L) was added. After heating and stirring the reaction solution at 45 ° C. for 20 hours,
After cooling to 30 ° C., the solvent was distilled off under reduced pressure. Dichloromethane (17.8 L) was added, and the solvent was again distilled off under reduced pressure. A slurry solution was prepared with dichloromethane (8.3 L) and allowed to cool to 0 ° C. On the other hand, the above slurry solution was added to a dichloromethane solution (6.1 L) of tert-butylamine (1.30 Kg) cooled to 0 ° C.
It was added over 1 hour at a temperature of not more than ℃. After further stirring at 23 ° C. for 1 hour, water (14.0 L) was added, the organic layer was separated, and washed once with water (3.5 L). The obtained organic layer was back-extracted twice with 1 N hydrochloric acid (7.0 L), and the obtained aqueous layer was treated with activated carbon. The reaction solution was neutralized (pHｐＨ7.5) with 29% sodium hydroxide (1.4 L),
Cooled to 0 ° C. The precipitated crystals were separated and dried to obtain white crystals of N-tertbutyltetrahydroisoquinolinecarboxamide (1.00 kg) (yield: 72.5%).

(Synthesis Example 5) Tetrahydroroisoquinoline carboxylic acid (10.0 g) and triphosgene (7.4 g)
Of tetrahydrofuran (100 mL) at 55 ° C.
The mixture was heated and stirred at 60 ° C. for 4 hours and at 65 ° C. for 1 hour.
After the solvent was distilled off under reduced pressure at 50 mL and cooled to room temperature, heptane (50 mL) was added. The precipitated crystals were collected by filtration, washed and heated once with heptane (10 mL), and dried under vacuum overnight to obtain NCA crystals (9.34 g) (yield: 8).
1.5%).

Synthesis Example 6 N-tertbutyltetrahydroisoquinolinecarboxamide (5.00 g) and 5
% Ru / C (0.50 g) in 2-propanol (33 m
L) The solution was stirred in an autoclave at room temperature at a hydrogen pressure of 30 atm, stirred at 100 ° C for 16 hours, cooled,
The catalyst was filtered off. The filtrate was evaporated under reduced pressure, and heptane (1
5 mL), and after activated carbon treatment, when gradually cooled to 0 ° C., crystals precipitated. This was filtered off to give N-tert-butyl-decahydro (4aS, 8aS) isoquinoline-3.
White crystals of (S) -carboxamide (3.14 g) were obtained (61.2% yield).

[0027]

According to the present invention, optically pure decahydro (4aS, 8aS) isoquinoline-3 (S) -carboxamide is obtained in a short step, at a high yield, using tetrahydroisoquinoline-3 (S) -carboxylic acid which is industrially available. It has become possible to produce derivatives.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁷ identification code FI C07M 7:00 (58) Investigated field (Int.Cl. ⁷ , DB name) C07D 217/26 B01J 23/46 301 C07B 53 / 00 C07D 498/04 105 C07B 61/00 300 C07M 7:00 CA (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. An N-carboxy compound represented by the following formula (2) by reacting a tetrahydroisoquinoline-3 (S) -carboxylic acid represented by the following formula (1) with any of phosgene, phosgene dimer, and triphosgene. After leading to anhydride (NCA), ammonia or C1-C1
And wherein the reaction with any of the 6 lower the primary Amin of, tetrahydroisoquinoline represented by the following formula (3) -3 (S) - method of manufacturing a carboxamide derivative. Embedded image (In the formula, R ₁ represents hydrogen or lower alkyl having 1 to 6 carbon atoms.) 2. Tetrahydroisoquinoline-3 (S)-
A carboxamide derivative was prepared by the method of claim 1.
A method for producing a decahydro (4aS, 8aS) isoquinoline-3 (S) -carboxamide derivative represented by the following formula (4) , wherein the derivative is subjected to a reduction reaction in the presence of a metal catalyst. Embedded image (In the formula, R ₁ represents hydrogen or lower alkyl having 1 to 6 carbon atoms.) 3. The method according to claim 2, wherein the metal catalyst is Ru. 4. The method according to claim 1, wherein R ₁ is a t-butyl group. 5. A tetrahydroisoquinoline-3 (S) -carboxylic acid N-carboxy anhydride represented by the following formula (2). Embedded image