DESCRIPTION
CRYSTALS OF MORPHINAN DERIVATIVE AND PROCESS
FOR PRODUCING THE SAME
Technical Field
The present invention relates to a crystal of 17-cyclopropylmethyl-3,14p-dihydroxy-
4,5a-epoxy-6P-[N-rnethyl-trans-3-(3-ruryl)acrylamido]morphinan hydrochloride which has an
analgesic, diuretic and antipruritic action and is useful as an active ingredient of analgesic,
diuretic and antipruritic agents, and a process for producing the same.
Background Art
17-Cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6P-[N-methyl-trans-3-(3-
furyl)acrylamido]moiphinan hydrochloride represented by the following formula (I):

is described in patent document 1. This compound has been demonstrated to be a compound
useful as an active ingredient of analgesic, diuretic and antipruritic agents. Patent document
1 specifically discloses the compound together with physiochemical properties thereof.
[Patent document 1]: JP Patent No. 2525552 (Example 68)
During intensive studies on the physical properties of the compound represented by the
above formula (I), the present inventors have found that whereas the compound (I) produced
according to Example 68 in patent document 1 is amorphous as shown in Figure 4, compound
(I) has crystal polymorphism, i.e., is present as an A-form, B-form or C-form crystal as
described later, when produced by a method different from the above method.
Generally, a compound having crystal polymorphism sometimes has physical
properties different for each crystal. Particularly in the medicinal field, there are known to be
1

differences in terms of solubility, solution velocity, stability, absorbability, or the like. Thus,
it is possible that even use of the same compound provides no desired potency thereof or leads
to a potency different from that predicted owing to a difference in crystal form, which causes
unforeseen circumstances. For that reason, there is a need for the provision of the compound
of consistent quality which can be expected to always have a constant potency.
Thus, when a compound having crystal polymorphism is used as a medicine, it is
necessary to stably provide the compound having uniform crystal form in order to ensure the
uniform quality and constant potency thereof.
The presence of a crystal of the compound represented by the above formula (I) has
previously been quite unknown, and patent document 1 also does not describe or suggest the
presence of a crystal or crystal polymorphism thereof.
Accordingly, the present inventors compared an amorphous form of compound (I)
prepared according to Example 68 in patent document 1 with a crystal of compound (I)
produced by a method different from the above method. As a result, it has been found that
whereas the amorphous compound is not consistent in quality after production and has low
purity, the crystal has no such problems and is excellent as an active ingredient of medicines
or as a preparation for analyzing medicines.
Disclosure of the Invention
The present invention encompasses the following invention.
(1) A crystal of 17-cyclopropylmethyl-3,14P-dihydroxy-4,5a-epoxy-6(3-[N-methyl-
trans-3-(3-furyl)acrylamido]morphinan hydrochloride.
(2) The crystal of the compound described in item (1) above, having highly intense
diffraction peaks at the positions of 29 of about 12.0°, about 18.9° and about 19.2° in a powder
X-ray diffraction pattern thereof.
(3) The crystal of the compound described in item (1) above, having highly intense
diffraction peaks at the positions of 20 of about 7.6°, about 15.9° and about 18.5° in a powder
X-ray diffraction pattern thereof.
2

(4) The crystal of the compound described in item (1) above, having highly intense
diffraction peaks at the positions of 28 of about 7.2°, about 17.2° and about 21.2° in a powder
X-ray diffraction pattern thereof.
(5) A process for producing the crystal described in item (1) or (2) above, comprising
reacting 17-cyclopropylmethyl-3,14pMihydroxy-4,5a-epoxy-6$-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan with hydrochloric acid in a good solvent, followed by mixing the
reaction solution with a poor solvent and stirring the mixture.
(6) The process described in item (5) above, wherein the good solvent is methanol and
the poor solvent is 2-propanol.
(7) A process for producing the crystal described in item (1) or (3) above, comprising
reacting 17-cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6p-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan with hydrochloric acid in water, followed by leaving the reaction
solution.
(8) A process for producing the crystal described in item (1) or (3) above, comprising
reacting 17-cyclopropylmethyl-3,14(3-dihydroxy-4,5a-epoxy-6p-[IS[-methyl-trans-3-(3-
furyl)acrylamido]morphinan with hydrochloric acid in water, followed by adding ethanol to
the reaction solution and then distilling off a part of the solvent under reduced pressure before
leaving or stirring the residue.
(9) A process for producing the crystal described in any one of items (1) to (4) above,
comprising recrystallizing 17-cyclopropylmethyl-3,14P-dihydroxy-4,5a-epoxy-6p-[N-methyl-
trans-3-(3-furyl)acrylamido]morphinan hydrochloride in a solvent selected from the group
consisting of methanol/2-propanol, ethanol/water, water and ethanol.

(10) A process for producing the crystal described in item (1) or (2) above, comprising
recrystallizing, in methanol/2-propanol, 17-cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-
6P-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride obtained by reacting 17-
cyclopropylmethyl-3,14P-dihydroxy-4,5 a-epoxy-6 P- [N-methyl-trans-3 -(3 -
furyl)acrylamido]morphinan with hydrochloric acid.
(11) A process for producing the crystal described in item (1) or (3) above, comprising
recrystallizing, in ethanol/water or water, 17-cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-
3

6(3-[N-methyl-trans-3-(3-furyl)acrylamido]moiphinan hydrochloride obtained by reacting 17-
cyclopropylmethyl-3,14P-dihydroxy-4,5a-epoxy-6p-[N-methyl-tfarlg-3-(3-
furyl)acrylamido]morphinan with hydrochloric acid.
(12) A process for producing the crystal described in item (1) or (4) above, comprising
recrystallizing, in ethanol, 17-cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6p-[N-methyl-
trans-3-(3-furyl)acrylamido]morphinan hydrochloride obtained by reacting 17-
cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6p-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan with hydrochloric acid.
The crystal of the present invention is optimal as a medicine intended to be constant in
the pH value of the product after production and to have consistent quality. The crystal also
has an extremely low content of the cis isomer as the prime impurity and is high in purity.
Best Mode for Carrying Out the Invention
The present invention provides a crystal of the compound represented by the above
formula (I).
The crystal of the present invention can be produced by any of processes described
below.

17-Cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6P-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan (hereinafter, in some cases, referred to as "free morphinan
derivative") is reacted with hydrochloric acid in a good solvent, followed by mixing the
reaction solution with a poor solvent and stirring the mixture.
Examples of the good solvent include methanol, ethanol and n-propanol; preferred is
methanol. Examples of the poor solvent include 2-propanol, 2-butanol, and t-butanol;
preferred is 2-propanol.
The amount of the good solvent used for the reaction with hydrochloric acid is typically
2 to 100 mL, preferably 8 to 12 mL based on lg of the free morphinan derivative.
The hydrochloric acid is typically used at a concentration of 0.1 to 12 N, preferably 1 to
2 N. The amount of hydrochloric acid is typically 0.9 to 1.5 equivalents, preferably 1.0 to 1.1
equivalents.
4

The volume ratio of the good solvent to the poor solvent is typically 1 to 3:5, preferably
1.5 to 2.5:5.
After mixing with the poor solvent and stirring the mixture, a seed crystal is preferably
added. Examples of the seed crystal used here include an A-form ciystal or C-form crystal.
After adding the seed crystal, the mixture is typically stirred for 1 to 30 days, preferably
1 to 5 days. The stirring is performed at 0 to 30°C.
The treatment is carried out using methanol as the good solvent and 2-propanol as the
poor solvent under the above conditions to provide an A-form crystal of the compound
represented by the above formula (I), i.e., a crystal having highly intense diffraction peaks at
the positions of 2G of about 12.0°, about 18.9° and about 19.2° in a powder X-ray diffraction
pattern thereof.

The free morphinan derivative is reacted with hydrochloric acid in water, followed by
leaving the reaction solution.
The amount of the water used as a solvent is typically 2 to 100 mL, preferably 6 to 8
mL based on 1 g of the free morphinan derivative.
The hydrochloric acid is typically used at a concentration of 0.1 to 12 N, preferably 1 to
2 N. The amount of hydrochloric acid is typically 0.9 to 1.5 equivalents, preferably 0.95 to
1.05 equivalents.
After adding the hydrochloric acid, a seed crystal may be optionally added. Examples
of the seed crystal used here include a B-form crystal in Example 4.
After adding the hydrochloric acid and optionally the seed crystal, the mixture is
typically left for 1 to 10 days, preferably 1 to 4 days.
The treatment is performed under the above conditions to provide a B-form crystal of
the compound represented by the above formula (I), i.e., a crystal having highly intense
diffraction peaks at the positions of 29 of about 7.6°, about 15.9° and about 18.5° in a powder
X-ray diffraction pattern thereof.

5

The free morphinan derivative is reacted with hydrochloric acid in water, followed by
adding ethanol to the reaction solution and then distilling off a part of the solvent under
reduced pressure before leaving or stirring the residue.
The amount of the water used as a solvent is typically 1 to 100 mL, preferably 2 to 4
mL based on 1 g of the free morphinan derivative.
The hydrochloric acid is typically used at a concentration of 0.1 to 12 N, preferably 1 N.
The amount of hydrochloric acid is typically 0.9 to 1.5 equivalents, preferably 0.95 to 1.05
equivalents.
The volume ratio of the water to the ethanol is typically 0.5 to 2:1, preferably 0.75 to
1.25:1.
After adding the ethanol, a part of the solvent is distilled off under reduced pressure;
here, the concentration degree is typically 2 to 10 times, preferably 3 to 5 times.
Then, the residue is typically left for 1 to 30 days, preferably 1 to 10 days.
The treatment is performed under the above conditions to provide a B-form crystal of
the compound represented by the above formula (I), i.e., a crystal having highly intense
diffraction peaks at the positions of 20 of about 7.6°, about 15.9° and about 18.5° in a powder
X-ray diffraction pattern thereof.

17-Cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6p-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan hydrochloride is recrystallized in a solvent selected from the
group consisting of methanol/2-propanol, ethanol/water, water and ethanol.
The process for producing the 17-cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6|3-
pSf-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride used in the fourth process is
not particularly limited; examples thereof include a process involving reacting the free
morphinan derivative with hydrochloric acid.
The volume ratio of methanol to 2-propanol in the methanol/2-propanol used as a
recrystallization solvent is typically 1 to 3:5, preferably 1.5 to 2.5:5. The volume ratio of
ethanol to water in the ethanol/water used as a recrystallization solvent is typically 0.5 to 2:1,
preferably 0.75 to 1.25:1.
6

The amount of the recrystallization solvent is typically 10 to 100 mL, preferably 30 to
40 mL based on 1 g of the hydrochloride.
The use of methanol/2-propanol as the recrystallization solvent provides the above A-
form crystal; the use of ethanol/water or water provides the B-form crystal.
The use of ethanol as the recrystallization solvent also provides a C-form crystal of the
compound represented by the above formula (I), i.e., a crystal having highly intense diffraction
peaks at the positions of 29 of about 7.2°, about 17.2° and about 21.2° in a powder X-ray
diffraction pattern thereof.
The resultant crystals can be isolated by washing and drying by an ordinary method.
The A-form, B-form and C-form crystals of the present invention have substantially the
same powder X-ray diffraction patterns as those shown in Figures 1, 2 and 3, respectively, and
substantially the same infrared absorption spectrum as those depicted in Figures 5, 6 and 7,
respectively.
Each spectral data should not be strictly interpreted since it can vary because of the
nature thereof. By way of example, because of the nature of powder X-ray diffraction
spectrum data, the diffraction angle 29 and the overall pattern are important in qualifying the
identity of crystals; the relative intensity can somewhat vary depending on the direction of
crystal growth, the size of crystal particles and the conditions of measurement. In addition,
the overall pattern is important in qualifying the identity of crystals also for infrared absorption
spectrum data; the pattern can somewhat vary depending on the conditions of measurement.
Thus, the crystal of the present invention includes that having a pattern totally similar to that
of data of powder X-ray diffraction spectrum or infrared absorption spectrum of the crystal of
the present invention.
Brief Description of the Drawings
Figure 1 is a powder X-ray diffraction pattern of an A-form crystal of 17-
cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6(3-[N-methyl-trans-3-(3-
furyl)acrylamido]moiphinan hydrochloride;
7

Figure 2 is a powder X-ray diffraction pattern of a B-form crystal of 17-
cyclopropylmethyl-3,14P-dihydroxy-4,5 a-epoxy-6 P- [N-methyl-trans-3 -(3 -
fuiyl)acrylamido]morphman hydrochloride;
Figure 3 is a powder X-ray diffraction pattern of a C-form crystal of 17-
cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6P-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan hydrochloride;
Figure 4 is a powder X-ray diffraction pattern of the amorphous powder of 17-
cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6p-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan hydrochloride disclosed in patent document 1;
Figure 5 is an infrared absorption spectrum of an A-form crystal of 17-
cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6p-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan hydrochloride;
Figure 6 is an infrared absorption spectrum of a B-form crystal of 17-
cyclopropylmethyl-3,14 p-dihydroxy-4,5 a-epoxy-6 p - [N-methyl-trans-3 -(3 -
furyl)acrylamido]morphinan hydrochloride;
Figure 7 is an infrared absorption spectrum of a C-form crystal of 17-
cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6p-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan hydrochloride; and
Figure 8 is an infrared absorption spectrum of the amorphous powder of 17-
cyclopropylmethyl-3,14p-dihydroxy-4,5 a-epoxy-6 p- [N-methyl-trans-3 -(3 -
furyl)acrylamido]morphinan hydrochloride disclosed in patent document 1.
This description includes part or all of the contents as disclosed in the description
and/or drawings of Japanese Patent Application No. 2005-110096, which is a priority
document of the present application.
Examples
The present invention is more specifically described below based on Examples.
However, the invention is not intended to be limited to these Examples.
Reference Example 1
Amorphous Powder of Compound (I)
8

There was taken 2.02 g of 17-cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6p-[N-
methyl-trans-3-(3-furyl)acrylamido]morphinan, which was then suspended in 20 mL of
ethanol, followed by adding 4.2 mL of 1 N hydrochloric acid before concentrating and diying
the mixture to provide 2.34 g of an amorphous powder of the title compound.
The infrared absorption spectrum thereof is shown in Figure 8. The powder X-iay
diffraction pattern thereof is shown in Figure 4.
Reference Example 2
Amorphous Powder of Compound (I)
There was taken 3.00 g of 17-cyclopropylmethyl-3,14p-dihydroxy-4,5oc-epoxy-6p-[N-
methyl-trans-3-(3-furyl)acrylamido]morphinan, which was then suspended in 30 mL of
ethanol, followed by adding 6.25 mL of 1 N hydrochloric acid before concentrating and drying
the mixture to provide 3.45 g of an amorphous powder of the title compound. This
compound had an infrared absorption spectrum agreeing with that of the compound obtained
in Reference Example 1.
Reference Example 3
Amorphous Powder of Compound (I)
There was taken 2.01 g of 17-cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6P-[N-
methyl-trans-3-(3-furyl)acrylamido]morphinan, which was then suspended in 20 mL of
ethanol, followed by adding 4.2 mL of 1 N hydrochloric acid before concentrating and drying
the mixture to provide 2.31 g of an amorphous powder of the title compound. This
compound had an infrared absorption spectrum agreeing with that of the compound obtained
in Reference Example 1.
Example 1
A-form Crystal of Compound (I)
There was taken 2.00 g of 17-cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6P-[N-
methyl-trans-3-(3-furyl)acrylamido]morphinan, which was then suspended in 20 mL of
methanol, followed by adding 4.4 mL of 1 N hydrochloric acid before filtration. The filtrate
was added to 50 mL of 2-propanol, which was then stirred. The C-form crystal in Example 7
or the A-form crystal in Example 2 or 3 was added as a seed crystal thereto, which was stirred
9

for 5 days and then filtered, followed by drying the crystal at room temperature. As a result,
1.82 g of an A-form crystal of the title compound was obtained.
The infrared absorption spectrum thereof is shown in Figure 5. The powder X-ray
diffraction pattern thereof is shown in Figure 1.
Example 2
A-form Crystal of Compound (I)
There was taken 20.65 g of 17-cyclopropylmethyl-3,14(3-dihydroxy-4,5a-epoxy-6p-
[N-methyl-trans-3-(3-furyl)acrylamido]morphinan, which was then suspended in 200 mL of
methanol, followed by adding 22.6 mL of 2 N hydrochloric acid before filtration. The filtrate
was added to 500 mL of 2-propanol, which was then stirred. The C-form crystal in Example
7 or the A-form crystal in Example 1 or 3 was added as a seed crystal thereto, which was
stirred overnight and then filtered, followed by drying the crystal at room temperature. As a
result, 16.66 g of an A-form crystal of the title compound was obtained. This compound had
a powder X-ray diffraction pattern and infrared absorption spectrum agreeing with those of the
compound obtained in Example 1.
Example 3
A-form Crystal of Compound (I)
There was taken 2.00 g of 17-cyclopropylmethyl-3,14P-dihydroxy-4,5a-epoxy-6p-[N-
methyl-trans-3-(3-furyl)acrylamido]morphinan, which was then suspended in 20 mL of
methanol, followed by adding 4.4 mL of 1 N hydrochloric acid before filtration. The filtrate
was added to 50 mL of 2-propanol, which was then stirred. The C-form crystal in Example 7
or the A-form crystal in Example 1 or 2 was added as a seed crystal thereto, which was stirred
overnight and then filtered, followed by drying the crystal at room temperature. As a result,
1.21 g of an A-form crystal of the title compound was obtained. This compound had an
infrared absorption spectrum agreeing with that of the compound obtained in Example 1.
Example 4
B-form Crystal of Compound (I)
There was taken 10.01 g of 17-cyclopropylmethyl-3,14(3-dihydroxy-4,5a-epoxy-6p-
[N-methyl-trans-3-(3-furyl)acrylamido]moiphinan, which was then suspended in 79 mL of
10

water, followed by adding 20.8 mL of 1 N hydrochloric acid. The mixture was left in the
dark for 4 daySj th§ resultant crystal was filtered and dried under reduced pressure at room
temperature to 40°C. As a result, 6.87 g of a B-form crystal of the title compound was
obtained.
The infrared absorption spectrum thereof is shown in Figure 6. The powder X-ray
diffraction pattern thereof is shown in Figure 2.
Example 5
B-form Crystal of Compound (I)
There was taken 2.01 g of 17-cyclopropylmethyl-3,14f3-dihydroxy-4,5a-epoxy-6p-[N-
methyl-trans-3-(3-furyl)acrylamido]morphinan, which was then suspended in 14 mL of water,
followed by adding 4.2 mL of 1 N hydrochloric acid. The B-form crystal in Example 4 or 6
was added as a seed crystal thereto, which was then left in the dark for 3 days; the resultant
crystal was filtered and dried under reduced pressure at room temperature to 40°C. As a
result, 0.61 g of a B-form crystal of the title compound was obtained. This compound had an
infrared absorption spectrum agreeing with that of the compound obtained in Example 4.
Example 6
B-form Crystal of Compound (I)
There was taken 2.01 g of 17-cyclopropylmethyl-3,14(i-dihydroxy-4,5a-epoxy-6p-[N-
methyl-trans-3-(3-furyl)acrylamido]morphinan, which was then suspended in 5.8 mL of water,
followed by adding 4.2 mL of 1 N hydrochloric acid. To the resultant solution was added 10
mL of ethanol, which was then concentrated under reduced pressure until the weight of the
solution was 6.3 g. The concentrate was left in a refrigerator for 8 days; the resultant crystal
was then filtered and dried under reduced pressure at room temperature. As a result, 1.67 g
of a B-form crystal of the title compound was obtained. This compound had a powder X-ray
diffraction pattern and an infrared absorption spectrum agreeing with those of the compound
obtained in Example 4.
Example 7
C-form Crystal of Compound (I)
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There was taken 2.02 g of 17-cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6(3-[N-
methyl-trans-3-(3-furyl)acrylamido]morphinan, which was then suspended in 100 mL of
ethanol, followed by adding 4.2 mL of 1 N hydrochloric acid. The resultant solution was
concentrated under reduced pressure and dried to provide a solid. Thereto was added 200
mL of ethanol, which was dissolved by warming at 40 to 50°C, followed by concentrating the
solution under reduced pressure so that the weight thereof was 17.31 g after the concentration.
The concentrate was left in the dark for 12 days; the resultant crystal was filtered and dried at
room temperature. As a result, 1.92 g of a C-form crystal of the title compound was obtained.
The infrared absorption spectrum thereof is shown in Figure 7. The powder X-ray
diffraction pattern thereof is shown in Figure 3.
Example 8
C-form Crystal of Compound (I)
There was taken 2.00 g of 17-cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6(3-[N-
methyl-trans-3-(3-furyl)acrylamido]morphinan, which was then suspended in 100 mL of
ethanol, followed by adding 4.2 mL of 1 N hydrochloric acid. The resultant solution was
concentrated under reduced pressure and dried to provide a solid. Thereto was added 200
mL of ethanol, which was dissolved by warming at 40 to 50°C, followed by concentrating the
solution under reduced pressure so that the weight thereof was 17.31 g after the concentration.
The C-form crystal in Example 7 was added as a seed crystal thereto, which was left in the
dark for 4 days; the resultant crystal was filtered and dried at room temperature. As a result,
1.77 g of a C-form crystal of the title compound was obtained. This compound had an
infrared absorption spectrum agreeing with that of the compound obtained in Example 7.
Test Example 1
The amorphous powder obtained in Reference Example 3 and the crystals obtained in
Examples 2, 5 and 8 were measured for purity using high performance liquid chromatography
(HPLC).
Column: YMC-Pack ODS-AM-303
12

Mobile phase: solution A: 50 mmol/L - sodium dihydrogenphosphate aqueous solution,
solution B: 50 mmol/L - sodium dihydrogenphosphate aqueous solution/acetonitrile = 60/40
(v/v)
Composition of solution B in the mobile phase: 0 to 30 min.: 0 -» 50%, 30 to 75 min.: 50 -»
100%, 75 to 90 min.: 100%, 90 to 120 min.: 0%
Flow rate: 1 mL/min.
Column temperature: 40°C
UV:210nm
As shown in Table 1, the crystals of 17-cyclopropylmethyl-3,14p-dihydroxy-4,5oc-
epoxy-6p-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride of the present
invention had high purity because of their extremely low contents of the cis isomer (17-
cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6p-[N-methyl-cis-3-(3-
furyl)acrylamido]morphinan) as the prime impurity contained in the compound.
[Table 1]
Content of Cis Isomer Contained in Compound

Compound Content of Cis
Isomer
Free-form 0.12%
Hydrochloride (Amorphous Powder Obtained in Reference
Example 3) 0.13%
Hydrochloride (A-form Crystal Obtained in Example 2) 0.05%
Hydrochloride (B-form Crystal Obtained in Example 5) 0.03%
Hydrochloride (C-form Crystal Obtained in Example 8) 0.09%
Test Example 2
There was taken 100 mg each of the amorphous powders obtained in Reference
Examples 1 to 3 and the A-form crystals obtained in Examples 1 to 3, to which 10 mL of
decarbonated water was added for dissolution, followed by measuring the pH. The results
are shown in Table 2.
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[Table 2]
pH Reproducibility after Production

Compound PH
Amorphous
Powder Reference Example 1 3.7

Reference Example 2 4.7

Reference Example 3 3.5
A-form Crystal Example 1 5.8

Example 2 5.4

Example 3 5.6
Whereas the amorphous powder of 17-cyclopropylmethyl-3,14(3-dihydroxy-4,5a-
epoxy-6p-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride had no
reproducibility in the pH after production, the A-form crystal of the present invention had a
constant pH value, which is very useful for achieving consistent quality.
All publications, patents, and patent applications cited in this application are intended
to be incorporated herein by reference in their entirety.
Industrial Applicability
The present invention is utilized in the medicinal field.
14

CLAIMS
1. A crystal of 17-cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6p-[N-methyl-trans-
3-(3-furyl)acrylamido]morphinan hydrochloride.
2. The crystal of the compound according to claim 1, having highly intense diffraction
peaks at the positions of 26 of about 12.0°, about 18.9° and about 19.2° in a powder X-ray
diffraction pattern thereof.
3. The crystal of the compound according to claim 1, having highly intense diffraction
peaks at the positions of 2G of about 7.6°, about 15.9° and about 18.5° in a powder X-ray
diffraction pattern thereof.
4. The crystal of the compound according to claim 1, having highly intense diffraction
peaks at the positions of 2G of about 7.2°, about 17.2° and about 21.2° in a powder X-ray
diffraction pattern thereof.
5. A process for producing the crystal according to claim 1 or 2, comprising reacting 17-
cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6p-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan with hydrochloric acid in a good solvent, followed by mixing the
reaction solution with a poor solvent and stirring the mixture.
6. The process according to claim 5, wherein the good solvent is methanol and the poor
solvent is 2-propanol.
7. A process for producing the crystal according to claim 1 or 3, comprising reacting 17-
cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6p-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan with hydrochloric acid in water, followed by leaving the reaction
solution.
8. A process for producing the crystal according to claim 1 or 3, comprising reacting 17-
cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6p-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan with hydrochloric acid in water, followed by adding ethanol to
the reaction solution and then distilling off a part of the solvent under reduced pressure before
leaving or stirring the residue.
15

9. A process for producing the crystal according to any one of claims 1 to 4, comprising
recrystallizing 17-cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6p-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan hydrochloride in a solvent selected from the group consisting of
methanol/2-propanol, ethanol/water, water and ethanol.
10. A process for producing the crystal according to claim 1 or 2, comprising
recrystallizing, in methanol/2-propanol, 17-cyclopropylmethyl-3,14(3-dihydroxy-4,5a-epoxy-
6p-[N-methyl4rang-3-(3-ruryl)acrylamido]morphinan hydrochloride obtained by reacting 17-
cyclopropylmethyl-3,14(3-dihydroxy-4,5a-epoxy-6p-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan with hydrochloric acid.
16
11. A process for producing the crystal according to claim 1 or 3, comprising
recrystallizing, in ethanol/water or water, 17-cyclopropylmethyl-3,14(3-dihydroxy-4,5a-epoxy-
6P-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride obtained by reacting 17-
cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6p-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan with hydrochloric acid.
12. A process for producing the crystal according to claim 1 or 4, comprising
recrystallizing, in ethanol, 17-cyclopropylmethyl-3,14p-dihydroxy-4,5a-epoxy-6p-[N-methyl-
trans-3-(3-furyl)acrylamido]morphinan hydrochloride obtained by reacting 17-
cyclopropylmethyl-3,14p-dihydroxy-4,5 a-epoxy-6 p-[N-methyl-trans-3 -(3 -
furyl)acrylamido]morphinan with hydrochloric acid.

The present invention is directed to provide 17-cyclopropylmethyl-3,14β-dihydroxy-
4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride consistent in
quality after production and having high purity. A crystal of 17-cyclopropylmethyl-3,14β-
dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride
including a A-form, B-form or C-form crystal thereof, and a process for producing the same
are provided.